DOCSLIB.ORG

The Role of Mechanism of Action of CD200: CD200R1 Interaction In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Mechanism of Action of CD200: CD200R1 Interaction In The Role and Mechanism of Action of CD200:CD200R1 Interaction in Breast Cancer by Anna Podnos A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Anna Podnos 2015 The Role and Mechanism of Action of CD200:CD200R Interaction in Breast Cancer Anna Podnos PhD Institute of Medical Science University of Toronto 2015 Abstract Cancer cells can use immune inhibitory receptors to evade the host’s anti-tumour responses and establish immunosuppressive networks in the tumour microenvironment. In this thesis, we investigated the interaction between the immunosuppressive molecule CD200 with its receptor, CD200R1, in breast cancer. We found that CD200 is expressed in the local tumour microenvironment in human breast cancer patients and developed a mouse model to study the effect of CD200 on tumour growth and metastasis. Using mouse-derived EMT6 breast cancer cells and BALB/c female hosts, we explored the effects of overexpressing and silencing the expression of CD200 and CD200R1 in hosts and tumour cells. CD200 expression by host and tumour cells enhanced tumour growth and metastasis to draining lymph nodes (DLN). Silencing CD200 expression in EMT6 tumour cells led to a reduction in primary tumour size and metastasis, as well as an increase in anti-tumour cytotoxic responses in the host. Lack of CD200R1 expression in the host resulted in a marked decrease in breast cancer development and CD200R1-/- mice were able to mount specific anti-EMT6 immune response that could be adoptively transferred to wild type naïve hosts. In addition, we extended our findings to a model in which anti-tumour immunity was explored in EMT6 tumour-bearing ii hosts lacking CD200 expression and treated with a combination of immunotherapy with the non- conventional chemotherapeutic agent, metformin. The findings suggest that CD200 may be an important prognostic marker and a target for breast cancer treatment that could synergize with other therapies and improve outcomes in patients. iii Acknowledgments First and foremost, I would like to express my gratitude to my supervisor and mentor, Reg Gorczynski, for his unconditional support, patience, generosity, and guidance. His passion for science has fueled my interest in biomedical research, and his vivacious energy and sense of humour have motivated me and made my time in his laboratory an enjoyable experience that I will never forget. I would also like to thank my colleagues and lab mates, who have supported me through the ups and downs of research over the last five years. I would especially like to thank our lab manager and a great teacher, Ismat Khatri, who taught me everything I know in the lab and has become a close personal friend and mentor. I am grateful for the encouragement and help from lab members Olha Kos and Fang Zhu, who have been reliable and supportive throughout this journey. Also, I thank Hassan Sadozai and Ramzi Khattar for their help with planning experiments and editing my thesis. I thank my program advisory committee members, Shannon Dunn and David Spaner, for their helpful comments and suggestions that have made this work better and for their guidance in resolving lab related problems. I also thank the Institute of Medical Science, particularly Mingyao Li, Cindy Morshead, and the administrative staff, for helping me navigate complicated situations and complete my thesis. Finally, I am thankful to Gillian Einstein, who has been my mentor for the Collaborative Graduate Program in Women’s Health and has expanded my research interests during my PhD. I am eternally grateful to my fiancé, Tom, for believing in me, supporting me through the hard times, celebrating with me in good times, and editing countless copies of my thesis. I also want to thank my parents, who have taught me to work hard and persevere, and my little brother David, who can always put a smile on my face. Last but not least, I would like to give a shout- out to my dogs, Chuba and Xena, for their unconditional love and slobbery kisses. iv Contributions Dr. Reg Gorczynski1,2 assisted with limiting dilution assays, chromium release assays, and mouse injections. Dr. Ismat Khatri2 assisted with human and mouse sCD200 ELISAs and data analysis. Dr. Kai Yu2 helped with genotyping and maintaining animal colonies. Dr. Nuray Erin3 assisted with the mixed lymphocyte culture assays. The Ontario Tumour Bank provided the human breast cancer plasma and serum samples as well as histology sections. 1 Institute of Medical Science, University of Toronto, Toronto, ON, Canada 2 University Health Network, Toronto General Hospital, Toronto, ON, Canada 3Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya City, Antalya, Turkey v Table of Contents Acknowledgments .......................................................................................................................... iv Contributions ................................................................................................................................... v Table of Contents ........................................................................................................................... vi List of Tables .................................................................................................................................. x List of Figures ................................................................................................................................ xi List of Abbreviations ................................................................................................................... xiv List of Appendices ....................................................................................................................... xix Chapter 1 Introduction and literature overview .............................................................................. 1 1 Introduction and literature overview .......................................................................................... 1 1.1 Cancer and the immune system .......................................................................................... 1 1.1.1 Immunity and cancer ............................................................................................... 1 1.1.2 Tumour microenvironment ..................................................................................... 2 1.1.3 Non-immune cells in the tumour microenvironment .............................................. 5 1.1.4 Innate immunity in cancer ...................................................................................... 7 1.1.5 Adaptive immunity in cancer ................................................................................ 11 1.1.6 Immune inhibitory receptors in the tumour microenvironment ............................ 19 1.2 Metastasis and the immune system ................................................................................... 20 1.2.1 Metastasis is a hallmark of cancer ........................................................................ 20 1.2.2 Immunity and metastasis ....................................................................................... 22 1.3 Breast cancer ..................................................................................................................... 23 1.3.1 Clinical features of breast cancer .......................................................................... 23 1.3.2 Tumour microenvironment in breast cancer ......................................................... 28 1.3.3 Animal models of breast cancer ............................................................................ 37 vi 1.4 CD200 and CD200R ......................................................................................................... 42 1.4.1 CD200:CD200R overview .................................................................................... 42 1.4.2 CD200:CD200R in cancer .................................................................................... 43 1.5 EMT6 breast cancer model ............................................................................................... 47 1.6 Objectives and hypotheses ................................................................................................ 50 Chapter 2 Evidence for a role of tumour CD200 expression in breast cancer metastasis: decreased metastasis in CD200R1-/- mice or using EMT6siCD200 breast cancer cells ............... 52 2 Studies in WT and CD200R1-/- mice with EMT6, EMT6CD200tg, and EMT6shCD200 tumour cells .......................................................................................................................................... 52 2.1 Abstract ............................................................................................................................. 52 2.2 Introduction ....................................................................................................................... 53 2.3 Materials and methods ...................................................................................................... 55 2.3.1 Mice ...................................................................................................................... 55 2.3.2 Monoclonal antibodies .......................................................................................... 55 2.3.3 EMT6 breast tumour cells, induction of tumour growth in BALB/c mice, and limiting dilution assays ........................................................................................
Load more

Recommended publications
  • ENSG Gene Encodes Effector TCR Pathway Costimulation Inhibitory/Exhaustion Synapse/Adhesion Chemokines/Receptors
    ENSG Gene Encodes Effector TCR pathway Costimulation Inhibitory/exhaustion Synapse/adhesion Chemokines/receptors ENSG00000111537 IFNG IFNg x ENSG00000109471 IL2 IL-2 x ENSG00000232810 TNF TNFa x ENSG00000271503 CCL5 CCL5 x x ENSG00000139187 KLRG1 Klrg1 x ENSG00000117560 FASLG Fas ligand x ENSG00000121858 TNFSF10 TRAIL x ENSG00000134545 KLRC1 Klrc1 / NKG2A x ENSG00000213809 KLRK1 Klrk1 / NKG2D x ENSG00000188389 PDCD1 PD-1 x x ENSG00000117281 CD160 CD160 x x ENSG00000134460 IL2RA IL-2 receptor x subunit alpha ENSG00000110324 IL10RA IL-10 receptor x subunit alpha ENSG00000115604 IL18R1 IL-18 receptor 1 x ENSG00000115607 IL18RAP IL-18 receptor x accessory protein ENSG00000081985 IL12RB2 IL-12 receptor x beta 2 ENSG00000186810 CXCR3 CXCR3 x x ENSG00000005844 ITGAL CD11a x ENSG00000160255 ITGB2 CD18; Integrin x x beta-2 ENSG00000156886 ITGAD CD11d x ENSG00000140678 ITGAX; CD11c x x Integrin alpha-X ENSG00000115232 ITGA4 CD49d; Integrin x x alpha-4 ENSG00000169896 ITGAM CD11b; Integrin x x alpha-M ENSG00000138378 STAT4 Stat4 x ENSG00000115415 STAT1 Stat1 x ENSG00000170581 STAT2 Stat2 x ENSG00000126561 STAT5a Stat5a x ENSG00000162434 JAK1 Jak1 x ENSG00000100453 GZMB Granzyme B x ENSG00000145649 GZMA Granzyme A x ENSG00000180644 PRF1 Perforin 1 x ENSG00000115523 GNLY Granulysin x ENSG00000100450 GZMH Granzyme H x ENSG00000113088 GZMK Granzyme K x ENSG00000057657 PRDM1 Blimp-1 x ENSG00000073861 TBX21 T-bet x ENSG00000115738 ID2 ID2 x ENSG00000176083 ZNF683 Hobit x ENSG00000137265 IRF4 Interferon x regulatory factor 4 ENSG00000140968 IRF8 Interferon
    [Show full text]
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • 3034.Full.Pdf
    Characterization of the CD200 Receptor Family in Mice and Humans and Their Interactions with CD200 This information is current as Gavin J. Wright, Holly Cherwinski, Mildred Foster-Cuevas, of September 28, 2021. Gary Brooke, Michael J. Puklavec, Mike Bigler, Yaoli Song, Maria Jenmalm, Dan Gorman, Terri McClanahan, Man-Ru Liu, Marion H. Brown, Jonathon D. Sedgwick, Joseph H. Phillips and A. Neil Barclay J Immunol 2003; 171:3034-3046; ; Downloaded from doi: 10.4049/jimmunol.171.6.3034 http://www.jimmunol.org/content/171/6/3034 References This article cites 39 articles, 20 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/171/6/3034.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Characterization of the CD200 Receptor Family in Mice and Humans and Their Interactions with CD2001 Gavin J.
    [Show full text]
  • Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma
    Anatomy and Pathology Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma Sarah L. Lake,1 Sarah E. Coupland,1 Azzam F. G. Taktak,2 and Bertil E. Damato3 PURPOSE. To detect deletions and loss of heterozygosity of disease is fatal in 92% of patients within 2 years of diagnosis. chromosome 3 in a rare subset of fatal, disomy 3 uveal mela- Clinical and histopathologic risk factors for UM metastasis noma (UM), undetectable by fluorescence in situ hybridization include large basal tumor diameter (LBD), ciliary body involve- (FISH). ment, epithelioid cytomorphology, extracellular matrix peri- ϩ ETHODS odic acid-Schiff-positive (PAS ) loops, and high mitotic M . Multiplex ligation-dependent probe amplification 3,4 5 (MLPA) with the P027 UM assay was performed on formalin- count. Prescher et al. showed that a nonrandom genetic fixed, paraffin-embedded (FFPE) whole tumor sections from 19 change, monosomy 3, correlates strongly with metastatic death, and the correlation has since been confirmed by several disomy 3 metastasizing UMs. Whole-genome microarray analy- 3,6–10 ses using a single-nucleotide polymorphism microarray (aSNP) groups. Consequently, fluorescence in situ hybridization were performed on frozen tissue samples from four fatal dis- (FISH) detection of chromosome 3 using a centromeric probe omy 3 metastasizing UMs and three disomy 3 tumors with Ͼ5 became routine practice for UM prognostication; however, 5% years’ metastasis-free survival. to 20% of disomy 3 UM patients unexpectedly develop metas- tases.11 Attempts have therefore been made to identify the RESULTS. Two metastasizing UMs that had been classified as minimal region(s) of deletion on chromosome 3.12–15 Despite disomy 3 by FISH analysis of a small tumor sample were found these studies, little progress has been made in defining the key on MLPA analysis to show monosomy 3.
    [Show full text]
  • CD200 and Its Receptor, CD200R, Modulate Bone Mass Via the Differentiation of Osteoclasts
    CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts Weiguo Cui*†, Esteban Cuartas*, Juan Ke*‡, Qing Zhang*, Halldor B. Einarsson*, Jonathon D. Sedgwick§¶, Jun Liʈ, and Agne` s Vignery*,** *Department of Orthopedics and Rehabilitation, Yale School of Medicine, 310 Cedar Street, New Haven, CT 06510; §Schering–Plough Biopharma (DNAX), Palo Alto, CA 94304; and ʈDepartment of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 Edited by Richard A. Flavell, Yale University School of Medicine, New Haven, CT, and approved July 25, 2007 (received for review April 11, 2007) Fusion of macrophages is an essential step in the differentiation of plays a role in the recognition of self and in the fusion of macro- osteoclasts, which play a central role in the development and remod- phages (10). To gain further insight into the mechanism of mac- eling of bone. Osteoclasts are important mediators of bone loss, rophage fusion, we subjected fusing alveolar macrophages from rats which leads, for example, to osteoporosis. Macrophage fusion recep- to genome-wide oligonucleotide microarray analysis, and we dis- tor/signal regulatory protein ␣ (MFR/SIRP␣) and its ligand CD47, covered the expression of CD200 de novo at the onset of fusion. which are members of the Ig superfamily (IgSF), have been implicated CD200 also belongs to the IgSF and has a short cytoplasmic tail. in the fusion of macrophages. We show that CD200, which is not It is expressed on various types of mouse and human cells (see ref. expressed in cells that belong to the myeloid lineage, is strongly 11 for a review) and on mouse osteoblasts (12), but not on expressed in macrophages at the onset of fusion.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • A New Insight Into Viral Proteins As Immunomodulatory Therapeutic Agents
    Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir A new insight into viral proteins as Immunomodulatory therapeutic agents. KSHV vOX2 a homolog of human CD200 as a potent anti-inflammatory protein Maryam Mousavinezhad-Moghaddam 1, Abbas Ali Amin 2, Houshang Rafatpanah 3, Seyed Abdol Rahim Rezaee 4 * 1 Department of Physiology, Biology Division, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran 2 Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran 3 Immunology Research Centre, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran 4 Inflammation and Inflammatory Diseases Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran A R T I C L E I N F O A B S T R A C T Article type: Review article The physiologic function of the immune system is defence against infectious microbes and tumour Article history: cells, Therefore, need to have precise modulatory mechanisms to maintain the body homeostasis. The Received: Aug 12, 2014 mammalian cellular CD200 (OX2)/CD200R interaction is one of such modulatory mechanisms in which Accepted: Nov 13, 2014 myeloid and lymphoid cells are regulated. CD200 and CD200R molecules are membrane proteins that Keywords: their immunomodulatory effects are able to suppress inflammatory responses, particularly in the CD200 privilege sites such as CNS and eyes. Kaposi’s sarcoma-associated herpesvirus (KSHV), encodes a wide Immune modulation variety of immunoregulatory proteins which play central roles in modulating inflammatory and anti- KSHV inflammatory responses in favour of virus dissemination. One such protein is a homologue of the RGD human CD200, encoded by open reading frame (ORF) K14 and therefore called vOX2/vCD200.
    [Show full text]
  • Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
    Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A.
    [Show full text]
  • Review Article the Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis
    Hindawi Publishing Corporation Stem Cells International Volume 2016, Article ID 1908365, 13 pages http://dx.doi.org/10.1155/2016/1908365 Review Article The Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis Wessam E. Sharaf-Eldin,1,2 Nourhan Abu-Shahba,2,3 Marwa Mahmoud,1,2,3 and Nagwa El-Badri1 1 Center of Excellence of Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Sheikh Zayed District, 6thofOctoberCity,Giza12566,Egypt 2Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12411, Egypt 3Stem Cells Research Group, Centre of Excellence for Advanced Sciences, National Research Centre, Cairo 12411, Egypt Correspondence should be addressed to Nagwa El-Badri; [email protected] Received 12 July 2015; Accepted 21 September 2015 AcademicEditor:JoelC.Glover Copyright © 2016 Wessam E. Sharaf-Eldin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The effect of mesenchymal stem cells (MSCs) on bone formation has been extensively demonstrated through several in vitro and in vivo studies. However, few studies addressed the effect of MSCs on osteoclastogenesis and bone resorption. Under physiological conditions, MSCs support osteoclastogenesis through producing the main osteoclastogenic cytokines, RANKL and M-CSF. However, during inflammation, MSCs suppress osteoclast formation and activity, partly via secretion of the key anti- osteoclastogenic factor, osteoprotegerin (OPG). In vitro, co-culture of MSCs with osteoclasts in the presence of high concentrations of osteoclast-inducing factors might reflect the in vivo inflammatory pathology and prompt MSCs to exert an osteoclastogenic suppressive effect.
    [Show full text]
  • Molecular Analyses of Malignant Pleural Mesothelioma
    Molecular Analyses of Malignant Pleural Mesothelioma Shir Kiong Lo National Heart and Lung Institute Imperial College Dovehouse Street London SW3 6LY A thesis submitted for MD (Res) Faculty of Medicine, Imperial College London 2016 1 Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer that is strongly associated with asbestos exposure. Majority of patients with MPM present with advanced disease and the treatment paradigm mainly involves palliative chemotherapy and best supportive care. The current chemotherapy options are limited and ineffective hence there is an urgent need to improve patient outcomes. This requires better understanding of the genetic alterations driving MPM to improve diagnostic, prognostic and therapeutic strategies. This research aims to gain further insights in the pathogenesis of MPM by exploring the tumour transcriptional and mutational profiles. We compared gene expression profiles of 25 MPM tumours and 5 non-malignant pleura. This revealed differentially expressed genes involved in cell migration, invasion, cell cycle and the immune system that contribute to the malignant phenotype of MPM. We then constructed MPM-associated co-expression networks using weighted gene correlation network analysis to identify clusters of highly correlated genes. These identified three distinct molecular subtypes of MPM associated with genes involved in WNT and TGF-ß signalling pathways. Our results also revealed genes involved in cell cycle control especially the mitotic phase correlated significantly with poor prognosis. Through exome analysis of seven paired tumour/blood and 29 tumour samples, we identified frequent mutations in BAP1 and NF2. Additionally, the mutational profile of MPM is enriched with genes encoding FAK, MAPK and WNT signalling pathways.
    [Show full text]
  • Investigating the Role of PIR1 and CD200R1 in the Innate Immune Response to Viral Pathogens
    University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2017-05-30 Investigating the Role of PIR1 and CD200R1 in the Innate Immune Response to Viral Pathogens Christopher R. MacKay University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Immunity Commons, Immunology of Infectious Disease Commons, Pathogenic Microbiology Commons, and the Virology Commons Repository Citation MacKay CR. (2017). Investigating the Role of PIR1 and CD200R1 in the Innate Immune Response to Viral Pathogens. GSBS Dissertations and Theses. https://doi.org/10.13028/M2602R. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/901 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. INVESTIGATING THE ROLE OF PIR1 AND CD200R1 IN THE INNATE IMMUNE RESPONSE TO VIRAL PATHOGENS A Dissertation Presented by CHRISTOPHER ROBERT MACKAY Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 30, 2017 M.D./Ph.D. Program INVESTIGATING THE ROLE OF PIR1 AND CD200R1 IN THE INNATE IMMUNE RESPONSE TO VIRAL PATHOGENS A Dissertation Presented by CHRISTOPHER ROBERT MACKAY The signatures of the Dissertation Defense Committee signifies completion and approval as to style and content of the Dissertation Evelyn A.
    [Show full text]
  • Anti-CD200R1 Monoclonal Antibody, Clone OX-102 [FITC] (CABT-47295MR) This Product Is for Research Use Only and Is Not Intended for Diagnostic Use
    Anti-CD200R1 monoclonal antibody, clone OX-102 [FITC] (CABT-47295MR) This product is for research use only and is not intended for diagnostic use. PRODUCT INFORMATION Product Overview Mouse anti Rat CD200 Receptor 1 antibody, clone OX-102 recognizes the rat OX2 (CD200) receptor 1. This antigen is a heavily glycosylated 60-100kDa cell surface molecule expressed by cells of the myeloid lineage but not by T or B lymphocytes. Mouse anti Rat CD200 Receptor 1 antibody, clone OX-102 has been shown to block the interaction of OX2 receptor 1 with CD200. Flow Cytometry Use 10ul of the suggested working dilution to label 106 cells in 100ul. Specificity CD200R1 Immunogen Membrane fraction of thioglycollate-elicited rat peripheral cells. Isotype IgG1 Source/Host Mouse Species Reactivity Rat Clone OX-102 Conjugate FITC Applications FC Procedure Conjugated Antibodies Format Purified IgG conjugated to Fluorescein Isothiocyanate Isomer 1 (FITC) - liquid Size 100 μg Preservative See individual product datasheet Storage in frost free freezers is not recommended. This product is photosensitive and should be protected from light. Avoid repeated freezing and thawing as this may denature the antibody. Should this product contain a precipitate we recommend microcentrifugation before use. Warnings For research purposes only GENE INFORMATION 45-1 Ramsey Road, Shirley, NY 11967, USA Email: [email protected] Tel: 1-631-624-4882 Fax: 1-631-938-8221 1 © Creative Diagnostics All Rights Reserved Gene Name Cd200r1 CD200 receptor 1 [ Rattus norvegicus (Norway
    [Show full text]