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  • 1.
    Abu-Siniyeh, Ahmed
    et al.
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Owen, Dylan M.
    Kings Coll London, Dept Phys, London WC2R 2LS, England.;Kings Coll London, Randall Div Cell & Mol Biophys, London WC2R 2LS, England..
    Benzing, Carola
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    Rinkwitz, Silke
    Becker, Thomas S.
    Univ Sydney, Brain & Mind Res Inst, Sydney Med Sch, Sydney, NSW 2006, Australia.;Univ Sydney, Dept Hlth Sci, Sydney, NSW 2006, Australia..
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gaus, Katharina
    Univ New S Wales, Sch Med Sci, ARC Ctr Adv Mol Imaging, Sydney, NSW 2052, Australia.;Univ New S Wales, Australian Ctr NanoMed, Sydney, NSW 2052, Australia..
    The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis2016In: Traffic: the International Journal of Intracellular Transport, ISSN 1398-9219, E-ISSN 1600-0854, Vol. 17, no 1, p. 66-79Article in journal (Refereed)
    Abstract [en]

    The differential distribution of lipids between apical and basolateral membranes is necessary for many epithelial cell functions, but how this characteristic membrane organization is integrated within the polarity network during ductal organ development is poorly understood. Here we quantified membrane order in the gut, kidney and liver ductal epithelia in zebrafish larvae at 3-11 days post fertilization (dpf) with Laurdan 2-photon microscopy. We then applied a combination of Laurdan imaging, antisense knock-down and analysis of polarity markers to understand the relationship between membrane order and apical-basal polarity. We found a reciprocal relationship between membrane order and the cell polarity network. Reducing membrane condensation by exogenously added oxysterol or depletion of cholesterol reduced apical targeting of the polarity protein, aPKC. Conversely, using morpholino knock down in zebrafish, we found that membrane order was dependent upon the Crb3 and Par3 polarity protein expression in ductal epithelia. Hence our data suggest that the biophysical property of membrane lipid packing is a regulatory element in apical basal polarity.

  • 2.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    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.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 3.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Maria Leonor Seguardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGFR alpha signaling is required for alveolar development in the mouse lung2017In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 145, p. S147-S147Article in journal (Other academic)
  • 4.
    Andrae, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gouveia, Leonor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gallini, Radiosa
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fredriksson, Linda
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Nilsson, Ingrid
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Bengt R.
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Electron Microscopy Unit, S-40530 Gothenburg, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex2016In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 4, p. 461-474Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

  • 5.
    Aspelund, Aleksanteri
    et al.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Robciuc, Marius R.
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Karaman, Sinem
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, Kari
    Univ Helsinki, Wihuri Res Inst, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.;Univ Helsinki, Translat Canc Biol Program, Biomedicum Helsinki, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland..
    Lymphatic System in Cardiovascular Medicine2016In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 118, no 3, p. 515-530Article, review/survey (Refereed)
    Abstract [en]

    The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.

  • 6. 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.
    Francois, Mathias
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Saharinen, Pipsa
    Immonen, Ilkka
    Alitalo, Kari
    Therapeutic Insights to Lymphangiogenic Growth Factors2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, no S1, p. 19-19Article in journal (Other academic)
  • 7.
    Bartlett, Christina S.
    et al.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Jeansson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Quaggin, Susan E.
    Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA.;Northwestern Univ, Div Nephrol & Hypertens, Chicago, IL 60611 USA..
    Vascular Growth Factors and Glomerular Disease2016In: ANNUAL REVIEW OF PHYSIOLOGY, VOL 78, ANNUAL REVIEWS, 2016, p. 437-461Chapter in book (Refereed)
    Abstract [en]

    The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. VEGF, ANGPT, EGF, SEMA3A, TGF-beta, and CXCL12 signal in paracrine fashions between the podocytes, endothelium, and mesangium associated with the glomerular capillary bed to maintain filtration barrier function. In this review, we summarize the current understanding of these signaling pathways in the development and maintenance of the glomerulus and the progression of disease.

  • 8.
    Bentley, Katie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Computat Biol Lab, Boston, MA USA..
    The temporal basis of angiogenesis2017In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 372, no 1720, p. 1-11, article id 20150522Article in journal (Refereed)
    Abstract [en]

    The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated 'temporal regulators' have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that 'temporal adaptation' provides a novel account of organ/disease-specific vascular morphology and reveals 'timing' as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a 'temporal adaptation' perspective in vascular biology, and indeed other areas of biology where timing remains elusive. This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.

  • 9.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lipid transport and human brain development2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 7, p. 699-701Article in journal (Other academic)
    Abstract [en]

    How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood-brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma.

  • 10.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Transcriptional control of endothelial energy2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 529, no 7585, p. 160-161Article in journal (Other academic)
  • 11. Bianchi, Roberta
    et al.
    Teijeira, Alvaro
    Proulx, Steven T.
    Christiansen, Ailsa J.
    Seidel, Catharina D.
    Ruelicke, Thomas
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Haegerling, Rene
    Halin, Cornelia
    Detmar, Michael
    A Transgenic Prox1-Cre-tdTomato Reporter Mouse for Lymphatic Vessel Research2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0122976Article in journal (Refereed)
    Abstract [en]

    The lymphatic vascular system plays an active role in immune cell trafficking, inflammation and cancer spread. In order to provide an in vivo tool to improve our understanding of lymphatic vessel function in physiological and pathological conditions, we generated and characterized a tdTomato reporter mouse and crossed it with a mouse line expressing Cre recombinase under the control of the lymphatic specific promoter Prox1 in an inducible fashion. We found that the tdTomato fluorescent signal recapitulates the expression pattern of Prox1 in lymphatic vessels and other known Prox1-expressing organs. Importantly, tdTomato co-localized with the lymphatic markers Prox1, LYVE-1 and podoplanin as assessed by whole-mount immunofluorescence and FACS analysis. The tdTomato reporter was brighter than a previously established red fluorescent reporter line. We confirmed the applicability of this animal model to intravital microscopy of dendritic cell migration into and within lymphatic vessels, and to fluorescence-activated single cell analysis of lymphatic endothelial cells. Additionally, we were able to describe the early morphological changes of the lymphatic vasculature upon induction of skin inflammation. The Prox1-Cre-tdTomato reporter mouse thus shows great potential for lymphatic research.

  • 12. Bravi, Luca
    et al.
    Rudini, Noemi
    Cuttano, Roberto
    Giampietro, Costanza
    Maddaluno, Luigi
    Ferrarini, Luca
    Adams, Ralf H.
    Corada, Monica
    Boulday, Gwenola
    Tournier-Lasserve, Elizabeth
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lampugnani, Maria Grazia
    Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 27, p. 8421-8426Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-tomesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.

  • 13.
    Bàrbara, Laviña
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Castro, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Niaudet, Colin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Bert, Cruys
    Peter, Carmeliet
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. 4Computational Biology Laboratory, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
    Cord, Brakebusch
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defective endothelial cell migration in the absence of Cdc42 leads to capillary-venous malformations: Cdc42 and vascular malformationsManuscript (preprint) (Other academic)
  • 14.
    Carthy, Jon M.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
    Stoeter, Martin
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Bellomo, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Angelos
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moren, Anita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Kardassis, Dimitris
    Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece..
    Gahman, Timothy C.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Shiau, Andrew K.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Bickle, Marc
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Zerial, Marino
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed)
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

  • 15.
    Carvalho, Alexandra T. P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Gouveia, Leonor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kanna, Charan Raju
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Warmlander, Sebastian K. T. S.
    Platts, Jamie A.
    Kamerlin, Lynn Shina Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 12, p. 1604-1612Article in journal (Refereed)
    Abstract [en]

    We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.

  • 16.
    Castro, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ando, Koji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Álvarez-Aznar, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Brakebusch, Cord
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. AstraZeneca/Karolinska Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expressionManuscript (preprint) (Other academic)
  • 17.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tumor-Induced Local and Systemic Impact on Blood Vessel Function2015In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 418290Article, review/survey (Refereed)
    Abstract [en]

    Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils andmacrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects.

  • 18.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tumor-induced neutrophil extracellular traps-drivers of systemic inflammation and vascular dysfunction2016In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 5, no 3, article id e1098803Article in journal (Other academic)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are part of the innate immune defense against microbes, but their contribution to several non-infectious inflammatory conditions has recently been unraveled. We demonstrate that NETs accumulate in the peripheral circulation in tumor-bearing mice, causing systemic inflammation and vascular dysfuntion in organs not affected by tumor cells.

  • 19.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saupe, Falk
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 20.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Femel, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 21.
    Chiang, Ivy Kim-Ni
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Fritzsche, Martin
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Pichol-Thievend, Cathy
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Neal, Alice
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Holmes, Kelly
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Lagendijk, Anne
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Overman, Jeroen
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    D'Angelo, Donatella
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Omini, Alice
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    Hermkens, Dorien
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Lesieur, Emmanuelle
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Liu, Ke
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Ratnayaka, Indrika
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Corada, Monica
    FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy..
    Bou-Gharios, George
    Univ Liverpool, Inst Aging & Chron Dis, Liverpool L69 3GA, Merseyside, England..
    Carroll, Jason
    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK, Robinson Way, Cambridge CB2 0RE, England..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, IFOM, I-1620139 Milan, Italy.
    Schulte-Merker, Stefan
    Univ Munster, D-48149 Munster, Germany.;Westfalische Wilhelms Univ Munster WWU, Inst Cardiovasc Organogenesis & Regenerat, Fac Med, Mendelstr 7, D-48149 Munster, Germany.;CiM Cluster Excellence, Munster, Germany..
    Hogan, Benjamin
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Beltrame, Monica
    Univ Milan, Dipartimento Biosci, Via Celoria 26, I-20133 Milan, Italy..
    De Val, Sarah
    Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England..
    Francois, Mathias
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development2017In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 144, no 14, p. 2629-2639Article in journal (Refereed)
    Abstract [en]

    Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancerswere able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo. Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway-deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

  • 22.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    New Frontiers in VEGF/VEGFR Biology2015In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 52, p. 79-79Article in journal (Other academic)
  • 23.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    On the physiology of vascular permeability2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 215, p. 19-19Article in journal (Other academic)
  • 24.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vascular permeability - the essentials2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 135-143Article, review/survey (Refereed)
    Abstract [en]

    The vasculature, composed of vessels of different morphology and function, distributes blood to all tissues and maintains physiological tissue homeostasis. In pathologies, the vasculature is often affected by, and engaged in, the disease process. This may result in excessive formation of new, unstable, and hyperpermeable vessels with poor blood flow, which further promotes hypoxia and disease propagation. Chronic vessel permeability may also facilitate metastatic spread of cancer. Thus, there is a strong incentive to learn more about an important aspect of vessel biology in health and disease: the regulation of vessel permeability. The current review aims to summarize current insights into different mechanisms of vascular permeability, its regulatory factors, and the consequences for disease.

  • 25.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    VEGF receptor signal transduction - A brief update2016In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 86, p. 14-17Article, review/survey (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) signal transduction through receptor tyrosine lcinases VEGF receptor 1, -2 and -3 is of crucial importance for monocytes/macrophages, blood vascular endothelial and lymphatic endothelial cells both in physiology and in a number of pathologies notably cancer. This brief review summarizes the current status of VEGF receptor signaling with emphasis on in vivo data.

  • 26.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Hansson, Goran K.
    Royal Swedish Acad Sci, POB 50005, SE-10405 Stockholm, Sweden..
    Tracheobronchial transplantation: The Royal Swedish Academy of Sciences' concerns2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 387, no 10022, p. 942-942Article in journal (Refereed)
  • 27.
    Costa, Guilherme
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Harrington, Kyle I.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Lovegrove, Holly E.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Page, Donna J.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Asymmetric division coordinates collective cell migration in angiogenesis2016In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, no 12, p. 1292-+Article in journal (Refereed)
    Abstract [en]

    The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

  • 28.
    Cruys, Bert
    et al.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Wong, Brian W.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Kuchnio, Anna
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Verdegem, Dries
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cantelmo, Anna Rita
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Conradi, Lena-Christin
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vandekeere, Saar
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bouche, Ann
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cornelissen, Ivo
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vinckier, Stefan
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Merks, Roeland M. H.
    Ctr Wiskunde & Informat, Life Sci Grp, Sci Pk 123, NL-1098 XG Amsterdam, Netherlands.;Leiden Univ, Math Inst, Niels Bohrweg 1, NL-2333 CA Leiden, Netherlands..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, I-20139 Milan, Italy..
    Gerhardt, Holger
    Katholieke Univ Leuven, Vasc Patterning Lab, Dept Oncol, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Vasc Patterning Lab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;Max Delbruck Ctr Mol Med, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany..
    Dewerchin, Mieke
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Dept Pathol, Computat Biol Lab, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA..
    Carmeliet, Peter
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Glycolytic regulation of cell rearrangement in angiogenesis2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12240Article in journal (Refereed)
    Abstract [en]

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.

  • 29.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Magnusson, Peetra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Institute of Molecular Oncology, Milan, Italy (E.D., M.G.L.); Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy (M.G.L.).
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy..
    Lampugnani, Maria Grazia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. FIRC Inst Mol Oncol, Milan, Italy.;Ist Ric Farmacol Mario Negri, Milan, Italy..
    Deregulated TGF-beta/BMP Signaling in Vascular Malformations2017In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 121, no 8, p. 981-999Article, review/survey (Refereed)
    Abstract [en]

    Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-beta/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-beta/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-beta/BMP receptor complex and the second to increased signaling sensitivity to TGF-beta/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.

  • 30.
    Cuttano, Roberto
    et al.
    IFOM, Milan, Italy..
    Rudini, Noemi
    IFOM, Milan, Italy..
    Bravi, Luca
    IFOM, Milan, Italy..
    Corada, Monica
    IFOM, Milan, Italy..
    Giampietro, Costanza
    IFOM, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy..
    Papa, Eleanna
    IFOM, Milan, Italy..
    Morini, Marco Francesco
    IFOM, Milan, Italy..
    Maddaluno, Luigi
    IFOM, Milan, Italy..
    Baeyens, Nicolas
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Adams, Ralf H.
    Univ Munster, Max Planck Inst Mol Biomed, Fac Med, Dept Tissue Morphogenesis, D-48149 Munster, Germany..
    Jain, Mukesh K.
    Case Cardiovasc Res Inst, Cleveland, OH USA.;Harrington Heart & Vasc Inst, Cleveland, OH USA.;Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA.;Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Cleveland, OH USA..
    Owens, Gary K.
    Univ Virginia, Sch Med, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA..
    Schwartz, Martin
    Yale Cardiovasc Res Ctr, New Haven, CT USA..
    Lampugnani, Maria Grazia
    IFOM, Milan, Italy.;Mario Negri Inst Pharmacol Res, Milan, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. IFOM, Milan, Italy.;Univ Milan, Dept Oncol & Oncohematol, Milan, Italy..
    KLF4 is a key determinant in the development and progression of cerebral cavernous malformations2016In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 1, p. 6-24Article in journal (Refereed)
    Abstract [en]

    Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFb/BMP) signaling. However, the mechanism linking Ccm gene inactivation and TGFb/ BMP-dependent EndMT remains undefined. Here, we report that Ccm1 ablation leads to the activation of a MEKK3-MEK5-ERK5MEF2 signaling axis that induces a strong increase in Kruppel-like factor 4 (KLF4) in ECs in vivo. KLF4 transcriptional activity is responsible for the EndMT occurring in CCM1-null ECs. KLF4 promotes TGFb/BMP signaling through the production of BMP6. Importantly, in endothelial-specific Ccm1 and Klf4 double knockout mice, we observe a strong reduction in the development of CCM and mouse mortality. Our data unveil KLF4 as a therapeutic target for CCM.

  • 31.
    De La Fuente, Alerie Guzman
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Lange, Simona
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria..
    Silva, Maria Elena
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile..
    Gonzalez, Ginez A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Tempfer, Herbert
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Tendon & Bone Regenerat, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, Peter
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Univ Melbourne, Dept Surg, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia,Ophthalmol, Melbourne, Vic, Australia..
    Zhao, Chao
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Di Canio, Ludovica
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Trost, Andrea
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Ophthalmol Optometry & Res Program Expt Ophthalmo, A-5020 Salzburg, Austria..
    Bieler, Lara
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Zaunmair, Pia
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Rotheneichner, Peter
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    O'Sullivan, Anna
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Couillard-Despres, Sebastien
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Errea, Oihana
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Mäe, Maarja A.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Tianjin Med Univ, Key Lab Post Neuroinjury Neuro Repair & Regenerat, Tianjin Neurol Inst, Dept Neurosurg,Gen Hosp,Minist Educ & Tianjin Cit, Tianjin 300052, Peoples R China..
    Keller, Annika
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Batiz, Luis F.
    Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Los Andes, Fac Med, CIB, Santiago, Chile..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Aigner, Ludwig
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    Franklin, Robin J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Rivera, Francisco J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1755-1764Article in journal (Refereed)
    Abstract [en]

    The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  • 32.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Milan, Italy; niv Milan, Dept Oncol & Hematooncol, Milan, Italy.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden.
    Oligodendrocytes follow blood vessel trails in the brain Brain microvasculature is a scaffold for neuroglial migration2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 351, no 6271, p. 341-342Article in journal (Refereed)
  • 33.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Vasc Biol Unit, I-20129 Milan, Italy..
    Hirschi, Karen K.
    Yale Cardiovasc Res Ctr, Dept Internal Med, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Genet, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Biomed Engn, New Haven, CT 06511 USA..
    Simons, Michael
    Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, Dept Internal Med, 333 Cedar St, New Haven, CT 06511 USA.;Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06511 USA..
    The molecular basis of endothelial cell plasticity2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14361Article, review/survey (Refereed)
    Abstract [en]

    The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.

  • 34.
    Dias, Mariana
    et al.
    Theodor Kocher Inst, Bern, Switzerland..
    Coisne, Caroline
    Theodor Kocher Inst, Bern, Switzerland..
    Baden, Pascale
    Theodor Kocher Inst, Bern, Switzerland..
    Lazarevic, Ivana
    Theodor Kocher Inst, Bern, Switzerland..
    Francisco, David
    Univ Bern, Bern, Switzerland..
    Lyck, Ruth
    Theodor Kocher Inst, Bern, Switzerland..
    Enzmann, Gaby
    Theodor Kocher Inst, Bern, Switzerland..
    Deutsch, Urban
    Theodor Kocher Inst, Bern, Switzerland..
    Bruggmann, Remy
    Univ Bern, Bern, Switzerland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Uppsala, Sweden..
    Furuse, Mikio
    Natl Inst Physiol Sci, Okazaki, Aichi, Japan..
    Engelhardt, Britta
    Theodor Kocher Inst, Bern, Switzerland..
    Claudin 3-Deficient C57BL/6 Mice Display Intact Brain Barriers2017In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 54, p. 63-63Article in journal (Other academic)
  • 35.
    Ding, Bi-Sen
    et al.
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China.;Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Liu, Catherine H.
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA..
    Sun, Yue
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China..
    Chen, Yutian
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China..
    Swendeman, Steven L.
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA.;Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA..
    Jung, Bongnam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Chavez, Deebly
    Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Cao, Zhongwei
    Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, State Key Lab Biotherapy, Minist Educ,West China Univ Hosp 2, Chengdu, Peoples R China.;Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China.;Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Christoffersen, Christina
    Rigshosp, Dept Clin Biochem, Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark..
    Nielsen, Lars Bo
    Rigshosp, Dept Clin Biochem, Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.;Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark..
    Schwab, Susan R.
    NYU, Sch Med, Dept Pathol, Skirball Inst, New York, NY USA..
    Rafii, Shahin
    Weill Cornell Med, Ansary Stem Cell Inst, Div Regenerat Med, Dept Med, New York, NY USA..
    Hla, Timothy
    Cornell Univ, Dept Pathol & Lab Med, Ctr Vasc Biol, Weill Cornell Med, New York, NY 10021 USA.;Harvard Med Sch, Dept Surg, Boston Childrens Hosp, Vasc Biol Program, Boston, MA USA..
    HDL activation of endothelial sphingosine-1-phosphate receptor-1 (S1P(1)) promotes regeneration and suppresses fibrosis in the liver2016In: JCI Insight, ISSN 2379-3708, Vol. 1, no 21, article id e87058Article in journal (Refereed)
    Abstract [en]

    Regeneration of hepatic sinusoidal vasculature is essential for non-fibrotic liver regrowth and restoration of its metabolic capacity. However, little is known about how this specialized vascular niche is regenerated. Here we show that activation of endothelial sphingosine-1-phosphate receptor-1 (S1P 1) by its natural ligand bound to HDL (HDL-S1P) induces liver regeneration and curtails fibrosis. In mice lacking HDL-S1P, liver regeneration after partial hepatectomy was impeded and associated with aberrant vascular remodeling, thrombosis and peri-sinusoidal fibrosis. Notably, this "maladaptive repair" phenotype was recapitulated in mice that lack S1P 1 in the endothelium. Reciprocally, enhanced plasma levels of HDL-S1P or administration of SEW2871, a pharmacological agonist specific for S1P 1 enhanced regeneration of metabolically functional vasculature and alleviated fibrosis in mouse chronic injury and cholestasis models. This study shows that natural and pharmacological ligands modulate endothelial S1P 1 to stimulate liver regeneration and inhibit fibrosis, suggesting that activation of this pathway may be a novel therapeutic strategy for liver fibrosis.

  • 36.
    Ebarasi, Lwaki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ashraf, Shazia
    Bierzynska, Agnieszka
    Gee, Heon Yung
    McCarthy, Hugh J.
    Lovric, Svjetlana
    Sadowski, Carolin E.
    Pabst, Werner
    Vega-Warner, Virginia
    Fang, Humphrey
    Koziell, Ania
    Simpson, Michael A.
    Dursun, Ismail
    Serdaroglu, Erkin
    Levy, Shawn
    Saleem, Moin A.
    Hildebrandt, Friedhelm
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed)
    Abstract [en]

    Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

  • 37.
    Eleftheriou, Nikolas M.
    et al.
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Sjolund, Jonas
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Bocci, Matteo
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Cortez, Eliane
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Lee, Se-Jin
    Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA..
    Cunha, Sara I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Pietras, Kristian
    Lund Univ, Div Translat Canc Res, Dept Lab Med, Lund, Sweden..
    Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-beta signaling2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 51, p. 84314-84325Article in journal (Refereed)
    Abstract [en]

    Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-beta family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown. Furthermore, the knockout of Gdf2 (BMP9), the primary ligand for ALK1 and endoglin, exhibited a mixed phenotype from each of ALK1 and endoglin deficiencies; overall primary tumor burden decreased, but hepatic metastases increased. Tumors lacking BMP9 display a hyperbranching vasculature, and an increase in vascular mesenchymal-marker expression, which may be implicit in the increase in metastases. Taken together, our work cautions against singular blockade of BMP9 and instead demonstrates the utility of dual blockade of ALK1 and endoglin as a strategy for anti-angiogenic therapy in PanNET.

  • 38.
    Erba, Benedetta Gaia
    et al.
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Gruppi, Cristian
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Corada, Monica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy.;Cogentech, Hystopatol Unit, Milan, Italy..
    Rosti, Vittorio
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Bartalucci, Niccolo'
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Villeval, Jean-Luc
    Inst Gustave Roussy, INSERM, U1009, Villejuif, France.;Univ Paris XI, Villejuif, France..
    Vannucchi, Alessandro Maria
    Univ Florence, Sect Haematol, Dept Med & Surg Care, Florence, Italy..
    Barosi, Giovanni
    Policlin San Matteo Fdn, Ctr Study & Treatment Myelofibrosis, Ctr Study Myelofibrosis, Biotechnol Res Labs,Ist Ricovero & Cura Carattere, Pavia, Italy..
    Balduini, Alessandra
    Univ Pavia, Dept Mol Med, Pavia, Italy..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol IFOM Fdn, Vasc Biol Lab, Milan, Italy..
    Endothelial-to-Mesenchymal Transition in Bone Marrow and Spleen of Primary Myelofibrosis2017In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 8, p. 1879-1892Article in journal (Refereed)
    Abstract [en]

    Primary myelofibrosis is characterized by the development of fibrosis in the bone marrow that contributes to ineffective hematopoiesis. Bone marrow fibrosis is the result of a complex and not yet fully understood interaction among megakaryocytes, myeloid cells, fibroblasts, and endothelial cells. Here, we report that >30% of the endothelial cells in the small vessels of the bone marrow and spleen of patients with primary myelofibrosis have a mesenchymal phenotype, which is suggestive of the process known as endothelial-to-mesenchymal transition (EndMT). EndMT can be reproduced in vitro by incubation of cultured endothelial progenitor cells or spleen-derived endothelial cells with inflammatory cytokines. Megakaryocytes appear to be implicated in this process, because EndMT mainly occurs in the microvessels close to these cells, and because megakaryocyte-derived supernatant fluid can reproduce the EndMT switch in vitro. Furthermore, EndMT is an early event in a JAK2-V617F knock-in mouse model of primary myelofibrosis. Overall, these data show for the first time that microvascular endothelial cells in the bone marrow and spleen of patients with primary myelofibrosis show functional and morphologic changes that are associated to the mesenchymal phenotype.

  • 39.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Moreno, Rafael
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alemany, Ramon
    IDIBELL Inst Catala Oncol, Barcelona, Spain..
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Activating CD40 While Inhibiting IL6R Induces Cytokine Production without PDL1 Upregulation in DCs2017In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 25, no 5 S1, p. 54-54Article in journal (Other academic)
  • 40.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moreno, R
    Milenova, I. Yoanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liljenfeldt, L
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dieterich, L C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, H
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alemany, R
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment2017In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 24, no 2, p. 92-103Article in journal (Refereed)
    Abstract [en]

    CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.

  • 41.
    Falkevall, Annelie
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Mehlem, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Palombo, Isolde
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Sahlgren, Benjamin Heller
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden.; Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, S-14186 Stockholm, Sweden.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ytterberg, A. Jimmy
    Karolinska Inst, Div Physiol Chem 1, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden.;Karolinska Inst, Rheumatol Unit, Dept Med, S-17176 Stockholm, Sweden..
    Olauson, Hannes
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Renal Med, S-14186 Stockholm, Sweden..
    Axelsson, Jonas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Apheresis & Stem Cell Handling, S-14186 Stockholm, Sweden..
    Sundelin, Birgitta
    Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Patrakka, Jaakko
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, KI AZ Integrated CardioMetabol Ctr ICMC, S-14157 Huddinge, Sweden..
    Scotney, Pierre
    CSL Ltd, Parkville, Vic 3052, Australia..
    Nash, Andrew
    CSL Ltd, Parkville, Vic 3052, Australia..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease2017In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 25, no 3, p. 713-726Article in journal (Refereed)
    Abstract [en]

    Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.

  • 42.
    Femel, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huijbers, Elisabeth JM
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Roswall, Pernilla
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pietras, Kristian
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer.2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 23, p. 12418-12427Article in journal (Refereed)
    Abstract [en]

    Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.

  • 43.
    Fernandez-Alonso, R.
    et al.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Martin-Lopez, M.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Gonzalez-Cano, L.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Garcia, S.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Castrillo, F.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    Diez-Prieto, I.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Univ Leon, Dept Med Cirugia & Anat Vet, E-24071 Leon, Spain..
    Fernandez-Corona, A.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Lorenzo-Marcos, M. E.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain.;Complejo Hosp Leon, Leon 24071, Spain..
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden.;Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75185 Uppsala, Sweden..
    Marques, M.
    Univ Leon, Inst Desarrollo Ganadero, E-24071 Leon, Spain..
    Marin, M. C.
    Univ Leon, Dept Biol Mol, Inst Biomed IBIOMED, E-24071 Leon, Spain..
    p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGF beta signaling2015In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 22, no 8, p. 1287-+Article in journal (Refereed)
    Abstract [en]

    Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-beta and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.

  • 44.
    Franzen, Oscar
    et al.
    Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Ermel, Raili
    Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia..
    Sukhavasi, Katyayani
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Jain, Rajeev
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Jain, Anamika
    Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden.
    Giannarelli, Chiara
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Kovacic, Jason C.
    Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA..
    Ruusalepp, Arno
    Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia.;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia.;Clin Gene Networks AB, Stockholm, Sweden..
    Skogsberg, Josefin
    Karolinska Inst, Dept Med Biochem & Biophys, Solna, Sweden..
    Hao, Ke
    Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA.;Clin Gene Networks AB, Stockholm, Sweden..
    Bjoerkegren, Johan L. M.
    Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden.;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, Tartu, Estonia.;Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA.;Clin Gene Networks AB, Stockholm, Sweden..
    Global analysis of A-to-I RNA editing reveals association with common disease variants2018In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 6, article id e4466Article in journal (Refereed)
    Abstract [en]

    RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.

  • 45.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Huusko, Jenni
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Yla-Herttuala, Seppo
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160930Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

  • 46.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Lindblom, Per
    Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
    Bondjers, Cecilia
    Gothenburg Univ, Sahlgrenska Acad, Dept Med Biochem, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice2016In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 349, no 2, p. 282-290Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) contribute to normal heart development. Deficient or abnormal expression of Pdgf and Pdgfr genes have a negative impact on cardiac development and function. The cellular effects of PDGFs in the hearts of Pdgf/Pdgfr mutants and the pathogenesis of the resulting abnormalities are poorly understood, but different PDGF isoforms induce varying effects. Here, we generated three new transgenic mouse types which complete a set of studies, where all different PDGF ligands have been expressed under the same heart specific alpha-myosin heavy chain promoter. Transgenic expression of the natural isoforms of Pdgfa and Pdgfb resulted in isoform specific fibrotic reactions and cardiac hypertrophy. Pdgfa overexpression resulted in a severe fibrotic reaction with up to 8-fold increase in cardiac size, leading to lethal cardiac failure within a few weeks after birth. In contrast, Pdgfb overexpression led to focal fibrosis and moderate cardiac hypertrophy. As PDGF-A and PDGF-B have different affinity for the two PDGF receptors, we analyzed the expression of the receptors and the histology of the fibrotic hearts. Our data suggest that the stronger fibrotic effect generated by Pdgfa overexpression was mediated by Pdgfra in cardiac interstitial mesenchymal cells, i.e. the likely source of extracellular matrix depostion and fibrotic reaction. The apparent sensitivity of the heart to ectopic PDGFR alpha agonists supports a role for endogenous PDGFRa agonists in the pathogenesis of cardiac fibrosis.

  • 47.
    Gardenier, Jason C.
    et al.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Hespe, Geoffrey E.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Kataru, Raghu P.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Savetsky, Ira L.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Torrisi, Jeremy S.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Nores, Gabriela D. Garcia
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Dayan, Joseph J.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Chang, David
    Univ Chicago Med & Biol Sci, Sect Plast & Reconstruct Surg, Chicago, IL USA..
    Zampell, Jamie
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid, Spain..
    Mehrara, Babak J.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema2016In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 15, article id e84095Article in journal (Refereed)
    Abstract [en]

    Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used Cre-lox mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4(+) cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.

  • 48.
    Georganaki, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vascular targeting for enhanced cancer immunotherapy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.

    The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.

    In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.

    In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.

    Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.

    List of papers
    1. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Open this publication in new window or tab >>VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation
    Show others...
    2015 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 29, no 1, p. 227-238Article in journal (Refereed) Published
    Abstract [en]

    Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) signaling pathway is in clinical use, but its effect on vascular function and the tumor microenvironment is poorly understood. Here, we investigate cross-talk between VEGF and proinflammatory TNF-α signaling in endothelial cells and its impact on leukocyte recruitment. We found that cotreatment with VEGF decreased TNF-α-induced Jurkat cell adhesion to human microvascular endothelial cells by 40%. This was associated with inhibition of TNF-α-mediated regulation of 86 genes, including 2 T-lymphocyte-attracting chemokines, CXCL10 and CXCL11 [TNF-α concentration 1 ng/ml; 50% inhibition/inhibitory concentration (IC50) VEGF, 3 ng/ml]. Notably, VEGF directly suppressed TNF-α-induced gene expression through negative cross-talk with the NF-κB-signaling pathway, leading to an early decrease in IFN regulatory factor 1 (IRF-1) expression and reduced phosphorylation of signal transducer and activator of transcription 1 (p-Stat1) at later times. Inhibition of VEGF signaling in B16 melanoma tumor-bearing mice by sunitinib treatment resulted in up-regulation of CXCL10 and CXCL11 in tumor vessels, accompanied by up to 18-fold increased infiltration of CD3(+) T-lymphocytes in B16 tumors. Our results demonstrate a novel role of VEGF in negative regulation of NF-κB signaling and endothelial activation in the tumor microenvironment and provide evidence that pharmacological inhibition of VEGF signaling enhances T-lymphocyte recruitment through up-regulation of chemokines CXCL10 and CXCL11.-Huang, H., Langenkamp, E., Georganaki, M., Loskog, A., Fuchs, P. F., Dieterich, L. C., Kreuger, J., Dimberg, A. VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-239496 (URN)10.1096/fj.14-250985 (DOI)000347378600022 ()25361735 (PubMedID)
    Note

    Författare två och tre delar andraförfattarskapet.

    Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2018-01-17Bibliographically approved
    2. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Open this publication in new window or tab >>Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
    Show others...
    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 31, p. 50277-50289Article in journal (Refereed) Published
    Abstract [en]

    CD40-activating immunotherapy has potent antitumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by immunosuppressive cells in the tumor and by endothelial anergy inhibiting recruitment of T-cells. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib decreased tumor growth and improved survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb led to increased activation of CD11c(+) dendritic cells in the tumor draining lymph node, while sunitinib treatment reduced vessel density and decreased accumulation of CD11b(+)Gr1(+) myeloid derived suppressor cells. The expression of ICAM-1 and VCAM-1 adhesion molecules was up-regulated on tumor endothelial cells only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced intratumoral infiltration of CD8(+) cytotoxic T-cells. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exerts potent complementary antitumor effects mediated by dendritic cell activation, a reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T-cells.

    Keyword
    CD40, sunitinib, MDSC, endothelial activation, T-cell
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-308035 (URN)10.18632/oncotarget.10364 (DOI)000385422000111 ()
    Funder
    EU, FP7, Seventh Framework Programme, 317445Swedish Childhood Cancer FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
    Available from: 2016-11-24 Created: 2016-11-23 Last updated: 2018-02-23Bibliographically approved
    3. Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Open this publication in new window or tab >>Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-339104 (URN)
    Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-01-17
    4. Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
    Open this publication in new window or tab >>Loss of tumor vessel marker ELTD1 (ADGRL4) reduces vascular abnormality and enhances tumor growth
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-339107 (URN)
    Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-01-17
    5. Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
    Open this publication in new window or tab >>Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responses
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-339110 (URN)
    Available from: 2018-01-16 Created: 2018-01-16 Last updated: 2018-01-17
  • 49.
    Georganaki, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Karampatzakis, Alexandros
    University of Manchester, Manchester Collaborative Centre for Inflammation Research.
    Tuit, Sander
    University of Bonn, Life and Medical Science Institute.
    Fotaki, Grammatiki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    van Hooren, Luuk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lugano, Roberta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kaunisto, Aura
    Novo Nordisk A/S, Denmark.
    Ellmark, Peter
    Alligator Bioscience AB.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schultze, Joachim
    University of Bonn, Life and Medical Science Institute.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tumor endothelial up-regulation of IDO1 is an immunosuppressive feedback mechanism that limits the response to CD40-stimulating immunotherapyManuscript (preprint) (Other academic)
  • 50.
    Georganaki, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    van Hooren, Luuk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Induction of tertiary lymphoid organ-like structures in glioma promotes efficient anti-tumor immune responsesManuscript (preprint) (Other academic)
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