DOCSLIB.ORG

Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma This information is current as Yasuhiro Mouri, Masashi Yano, Miho Shinzawa, Yusuke of September 26, 2021. Shimo, Fumiko Hirota, Yumiko Nishikawa, Takuro Nii, Hiroshi Kiyonari, Takaya Abe, Hisanori Uehara, Keisuke Izumi, Koji Tamada, Lieping Chen, Josef M. Penninger, Jun-ichiro Inoue, Taishin Akiyama and Mitsuru Matsumoto J Immunol 2011; 186:5047-5057; Prepublished online 25 Downloaded from March 2011; doi: 10.4049/jimmunol.1003533 http://www.jimmunol.org/content/186/9/5047 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/03/25/jimmunol.100353 Material 3.DC1 References This article cites 54 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/186/9/5047.full#ref-list-1 Why The JI? Submit online. by guest on September 26, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma Yasuhiro Mouri,* Masashi Yano,* Miho Shinzawa,† Yusuke Shimo,† Fumiko Hirota,* Yumiko Nishikawa,* Takuro Nii,* Hiroshi Kiyonari,‡ Takaya Abe,‡ Hisanori Uehara,x Keisuke Izumi,x Koji Tamada,{ Lieping Chen,‖ Josef M. Penninger,# Jun-ichiro Inoue,† Taishin Akiyama,†,** and Mitsuru Matsumoto* It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-b receptor (LTbR), receptor activator for NF-kB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain Downloaded from enigmatic. In this study, we show that the LTbR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTbR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTbR and CD40 signals. Thus, the LTbR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity. The Journal of Immunology, 2011, 186: 5047–5057. http://www.jimmunol.org/ he thymus provides a microenvironment in which T cells Aire deficiency (5–8). The significance of TRA gene expression in gain the ability to discriminate between self and nonself the thymic stroma for the establishment of central tolerance has T (1, 2). Developing thymocytes recognizing self-Ags in been further supported by the fact that mice deficient in several the thymic stroma either develop into immunoregulatory T cells signal-transducing molecules and NF-kB components downstream or are deleted by apoptosis, depending on the strength and/or na- of TNFR superfamily (TNFRsf) members have a similar or, in ture of the reactivity with self-Ags (3). Medullary thymic epithelial many cases, more profound reduction of TRA gene expression (9– cells (mTECs) seem to play pivotal roles in this cross talk with 15), and it has been shown that embryonic thymi taken from these thymocytes by expressing a set of self-Ags (4). This scenario has mice induce autoimmune disease phenotypes when grafted into by guest on September 26, 2021 been supported by gene expression studies showing that mTECs recipient mice. In this regard, it is important to emphasize that, in are a specialized cell type in which promiscuous expression of contrast to Aire-deficient mice, the reduction of TRA gene ex- a broad range of tissue-restricted Ag (TRA) genes is an autono- pression in these mice is strongly associated with a defect in the mous property (1). Remarkably, mice deficient for autoimmune mTEC differentiation program; the thymi show easily discernable regulator (Aire), a mouse homolog of the gene responsible for the structural abnormalities such as a small medulla, a paucity of development of autoimmune polyendocrinopathy-candidiasis-ecto- mTECs including Aire-expressing cells, and loss of architectural dermal dystrophy in humans, show reduced expression of many, integrity of mTECs, as assessed by morphological observation though not all, TRA genes from mTECs, which has been impli- and flow cytometric analysis. Subsequently, one of the upstream cated in the development of autoimmune pathogenesis caused by TNFRsf members responsible for thymic organogenesis was iden- *Division of Molecular Immunology, Institute for Enzyme Research, The University Education, Culture, Sports, Science and Technology of Japan (to M.M., T.A., and J.I.), of Tokushima, Tokushima 770-8503, Japan; †Division of Cellular and Molecular and by the Takeda Science Foundation (to M.M.). Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Address correspondence and reprint requests to Prof. Mitsuru Matsumoto or Dr. ‡Laboratory for Animal Resources and Genetic Engineering, Center for Developmen- x Taishin Akiyama, Division of Molecular Immunology, Institute for Enzyme Re- tal Biology, RIKEN Kobe, Kobe 650-0047, Japan; Department of Molecular and search, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Environmental Pathology, Institute of Health Biosciences, The University of Tokush- { Japan (M.M.) or Division of Cellular and Molecular Biology, Institute of Medical ima Graduate School, Tokushima 770-8503, Japan; Marlene and Stewart Greene- ‖ Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, baum Cancer Center, University of Maryland, Baltimore, MD 21201; Depart- Japan (T.A.). E-mail addresses: [email protected] (M.M.) and taishin@ ment of Oncology and Institute for Cell Engineering, The Johns Hopkins University ims.u-tokyo.ac.jp (T.A.) School of Medicine, Baltimore, MD 21205; #Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria; and **Precursory Re- The online version of this article contains supplemental material. search for Embryonic Science and Technology, Japan Science and Technology Abbreviations used in this article: Aire, autoimmune regulator; 2-DG, 29-deoxygua- Agency, Saitama 332-0012, Japan nosine; DKO, double knockout; E, embryonic day; EpCAM, epithelial cell adhesion Received for publication October 25, 2010. Accepted for publication February 18, molecule; FTOC, fetal thymus organ culture; IKKa,IkB kinase a; K5, keratin 5; KI, 2011. knockin mice; KO, knockout; LTbR, lymphotoxin-b receptor; MHC II, MHC class II; mLT, membrane-bound form of lymphotoxin; mTEC, medullary thymic epithelial This work was supported in part by Grants-in-Aid for Scientific Research from the cell; NIK, NF-kB–inducing kinase; RANK, receptor activator for NF-kB; RANKL, Japan Society for the Promotion of Science and from the Ministry of Education, RANK ligand; Sap1, salivary protein 1; sLT, secreted form of lymphotoxin; TNFRsf, Culture, Sports, Science and Technology of Japan (to M.M.), by Grants-in-Aid for TNFR superfamily; TRA, tissue-restricted Ag; TRAF, TNFR-associated factor; Scientific Research from the Precursory Research for Embryonic Science and Tech- UEA-1, Ulex europaeus agglutinin 1. nology program of the Japan Science and Technology Agency (to T.A.), by a grant from the Japanese Society for the Promotion of Science (to T.A.), by a Cooperative Ó Research grant from the Institute for Enzyme Research, The University of Tokushima Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 (to M.M. and T.A.), by grants for Priority Area Research from the Ministry of www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003533 5048 LYMPHOTOXIN ELICITS THYMIC STROMAL RANK EXPRESSION tified as receptor activator for NF-kB (RANK) (16). These studies Thus, cytokine signals mediated by multiple TNFRsf members ex- clearly suggested a link between cytokine-mediated thymic or- hibit unique cooperation to achieve the mTEC organization re- ganogenesis and the establishment of central tolerance (1, 17). quired for establishment of self-tolerance in the thymus. Besides the individual role of each TNFRsf signal in the pro- duction and maintenance of mTECs, combined actions of multiple Materials and Methods TNFRsf members, RANK and CD40, have recently been dem- Mice onstrated (18) (see below). Ltbr-KO (accession number CDB0531K at the Center for Developmental Among the TNFRsf members studied
Load more

Recommended publications
  • Dimerization of Ltβr by Ltα1β2 Is Necessary and Sufficient for Signal
    Dimerization of LTβRbyLTα1β2 is necessary and sufficient for signal transduction Jawahar Sudhamsua,1, JianPing Yina,1, Eugene Y. Chiangb, Melissa A. Starovasnika, Jane L. Groganb,2, and Sarah G. Hymowitza,2 Departments of aStructural Biology and bImmunology, Genentech, Inc., South San Francisco, CA 94080 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2013 (received for review June 6, 2013) Homotrimeric TNF superfamily ligands signal by inducing trimers survival in a xenogeneic human T-cell–dependent mouse model of of their cognate receptors. As a biologically active heterotrimer, graft-versus-host disease (GVHD) (11). Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the TNFRSF members are typically activated by TNFSF-induced three unique potential receptor-binding interfaces in LTα1β2 trig- trimerization or higher order oligomerization, resulting in initiation ger signaling via LTβ Receptor (LTβR) resulting in lymphoid organ- of intracellular signaling processes including the canonical and ogenesis and propagation of inflammatory signals is poorly noncanonical NF-κB pathways (2, 3). Ligand–receptor interactions α β understood. Here we show that LT 1 2 possesses two binding induce higher order assemblies formed between adaptor motifs in sites for LTβR with distinct affinities and that dimerization of LTβR the cytoplasmic regions of the receptors such as death domains or α β fi by LT 1 2 is necessary and suf cient for signal transduction. The TRAF-binding motifs and downstream signaling components such α β β crystal structure of a complex formed by LT 1 2,LT R, and the fab as Fas-associated protein with death domain (FADD), TNFR1- fragment of an antibody that blocks LTβR activation reveals the associated protein with death domain (TRADD), and TNFR-as- lower affinity receptor-binding site.
    [Show full text]
  • The Unexpected Role of Lymphotoxin Β Receptor Signaling
    Oncogene (2010) 29, 5006–5018 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The unexpected role of lymphotoxin b receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development MJ Wolf1, GM Seleznik1, N Zeller1,3 and M Heikenwalder1,2 1Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Virology, Technische Universita¨tMu¨nchen/Helmholtz Zentrum Mu¨nchen, Munich, Germany The cytokines lymphotoxin (LT) a, b and their receptor genesis. Consequently, the inflammatory microenviron- (LTbR) belong to the tumor necrosis factor (TNF) super- ment was added as the seventh hallmark of cancer family, whose founder—TNFa—was initially discovered (Hanahan and Weinberg, 2000; Colotta et al., 2009). due to its tumor necrotizing activity. LTbR signaling This was ultimately the result of more than 100 years of serves pleiotropic functions including the control of research—indeed—the first observation that tumors lymphoid organ development, support of efficient immune often arise at sites of inflammation was initially reported responses against pathogens due to maintenance of intact in the nineteenth century by Virchow (Balkwill and lymphoid structures, induction of tertiary lymphoid organs, Mantovani, 2001). Today, understanding the underlying liver regeneration or control of lipid homeostasis. Signal- mechanisms of why immune cells can be pro- or anti- ing through LTbR comprises the noncanonical/canonical carcinogenic in different types of tumors and which nuclear factor-jB (NF-jB) pathways thus inducing cellular and molecular inflammatory mediators (for chemokine, cytokine or adhesion molecule expression, cell example, macrophages, lymphocytes, chemokines or proliferation and cell survival.
    [Show full text]
  • Targeting the Lymphotoxin-B Receptor with Agonist Antibodies As a Potential Cancer Therapy
    Research Article Targeting the Lymphotoxin-B Receptor with Agonist Antibodies as a Potential Cancer Therapy Matvey Lukashev,1 Doreen LePage,1 Cheryl Wilson,1 Ve´ronique Bailly,1 Ellen Garber,1 AlexLukashin, 1 Apinya Ngam-ek,1 Weike Zeng,1 Norman Allaire,1 Steve Perrin,1 Xianghong Xu,1 Kendall Szeliga,1 Kathleen Wortham,1 Rebecca Kelly,1 Cindy Bottiglio,1 Jane Ding,1 Linda Griffith,1 Glenna Heaney,1 Erika Silverio,1 William Yang,1 Matt Jarpe,1 Stephen Fawell,1 Mitchell Reff,1 Amie Carmillo,1 Konrad Miatkowski,1 Joseph Amatucci,1 Thomas Crowell,1 Holly Prentice,1 Werner Meier, 1 Shelia M. Violette,1 Fabienne Mackay,1 Dajun Yang,2 Robert Hoffman,3 and Jeffrey L. Browning1 1Departments of Immunobiology, Oncopharmacology, Molecular Engineering, Molecular Profiling, Molecular Discovery, Antibody Humanization, and Cellular Engineering, Biogen Idec, Cambridge, Massachusetts; 2Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; and 3AntiCancer, Inc., San Diego, California Abstract receptor (TRAILR) 1/2, death receptor (DR) 3, DR6, and possibly ectodermal dysplasia receptor (EDAR). These TNFRs harbor The lymphotoxin-B receptor (LTBR) is a tumor necrosis factor signaling adaptor motifs termed death domains that can initiate receptor family member critical for the development and the extrinsic apoptosis program. In addition, TNFRs of this group maintenance of various lymphoid microenvironments. Herein, can exert antitumor effects via other mechanisms that include we show that agonistic anti-LTBR monoclonal antibody (mAb) tumor sensitization to chemotherapeutic agents, activation of CBE11 inhibited tumor growth in xenograft models and antitumor immunity, and disruption of tumor-associated micro- potentiated tumor responses to chemotherapeutic agents.
    [Show full text]
  • Reactive Stroma in Human Prostate Cancer: Induction of Myofibroblast Phenotype and Extracellular Matrix Remodeling1
    2912 Vol. 8, 2912–2923, September 2002 Clinical Cancer Research Reactive Stroma in Human Prostate Cancer: Induction of Myofibroblast Phenotype and Extracellular Matrix Remodeling1 Jennifer A. Tuxhorn, Gustavo E. Ayala, Conclusions: The stromal microenvironment in human Megan J. Smith, Vincent C. Smith, prostate cancer is altered compared with normal stroma and Truong D. Dang, and David R. Rowley2 exhibits features of a wound repair stroma. Reactive stroma is composed of myofibroblasts and fibroblasts stimulated to Departments of Molecular and Cellular Biology [J. A. T., T. D. D., express extracellular matrix components. Reactive stroma D. R. R.] and Pathology [G. E. A., M. J. S., V. C. S.] Baylor College of Medicine, Houston, Texas 77030 appears to be initiated during PIN and evolve with cancer progression to effectively displace the normal fibromuscular stroma. These studies and others suggest that TGF-␤1isa ABSTRACT candidate regulator of reactive stroma during prostate can- Purpose: Generation of a reactive stroma environment cer progression. occurs in many human cancers and is likely to promote tumorigenesis. However, reactive stroma in human prostate INTRODUCTION cancer has not been defined. We examined stromal cell Activation of the host stromal microenvironment is pre- phenotype and expression of extracellular matrix compo- dicted to be a critical step in adenocarcinoma growth and nents in an effort to define the reactive stroma environ- progression (1–5). Several human cancers have been shown to ment and to determine its ontogeny during prostate cancer induce a stromal reaction or desmoplasia as a component of progression. carcinoma progression. However, the specific mechanisms of Experimental Design: Normal prostate, prostatic intra- stromal cell activation are not known, and the extent to which epithelial neoplasia (PIN), and prostate cancer were exam- stroma regulates the biology of tumorigenesis is not fully un- ined by immunohistochemistry.
    [Show full text]
  • Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates
    Research Article Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates David Gius,1 Margo C. Funk,2 Eric Y. Chuang,1 Sheng Feng,3 Phyllis C. Huettner,4 Loan Nguyen,2 C. Matthew Bradbury,1 Mark Mishra,1 Shuping Gao,1 Barbara M. Buttin,2 David E. Cohn,2 Matthew A. Powell,2 Neil S. Horowitz,2 Bradford P. Whitcomb,2 and JanetS. Rader 2 1Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; 3Division of Biostatistics; and 4Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri Abstract (CIN 1–3) and finally to squamous cell carcinoma antigen (SCCA) This study is the first comprehensive, integrated approach to have been well characterized. Histologically, CIN 1 consists of examine grade-specific changes in gene expression along the immature basal-type cells involving the lower third of the entire neoplastic spectrum of cervical intraepithelial neoplasia epithelium. In CIN 2, these immature basal-type cells involve more (CIN) in the process of cervical carcinogenesis. This was than the lower third, whereas CIN 3 involves the full thickness of the accomplished by identifying gene expression signatures of epithelium. In addition, higher CIN grades exhibit nuclear crowding, disease progression using cDNA microarrays to analyze RNA pleomorphism, loss of cell polarity, and increased mitotic activity from laser-captured microdissected epithelium and underlying (1). These transitions seemto be well conserved and, as such, stroma from normal cervix, graded CINs, cancer, and patient- provide an intriguing systemto use genomicsto identify the early matched normal cervical tissues.
    [Show full text]
  • Colposcopy of the Uterine Cervix
    THE CERVIX: Colposcopy of the Uterine Cervix • I. Introduction • V. Invasive Cancer of the Cervix • II. Anatomy of the Uterine Cervix • VI. Colposcopy • III. Histology of the Normal Cervix • VII: Cervical Cancer Screening and Colposcopy During Pregnancy • IV. Premalignant Lesions of the Cervix The material that follows was developed by the 2002-04 ASCCP Section on the Cervix for use by physicians and healthcare providers. Special thanks to Section members: Edward J. Mayeaux, Jr, MD, Co-Chair Claudia Werner, MD, Co-Chair Raheela Ashfaq, MD Deborah Bartholomew, MD Lisa Flowers, MD Francisco Garcia, MD, MPH Luis Padilla, MD Diane Solomon, MD Dennis O'Connor, MD Please use this material freely. This material is an educational resource and as such does not define a standard of care, nor is intended to dictate an exclusive course of treatment or procedure to be followed. It presents methods and techniques of clinical practice that are acceptable and used by recognized authorities, for consideration by licensed physicians and healthcare providers to incorporate into their practice. Variations of practice, taking into account the needs of the individual patient, resources, and limitation unique to the institution or type of practice, may be appropriate. I. AN INTRODUCTION TO THE NORMAL CERVIX, NEOPLASIA, AND COLPOSCOPY The uterine cervix presents a unique opportunity to clinicians in that it is physically and visually accessible for evaluation. It demonstrates a well-described spectrum of histological and colposcopic findings from health to premalignancy to invasive cancer. Since nearly all cervical neoplasia occurs in the presence of human papillomavirus infection, the cervix provides the best-defined model of virus-mediated carcinogenesis in humans to date.
    [Show full text]
  • Nomina Histologica Veterinaria, First Edition
    NOMINA HISTOLOGICA VETERINARIA Submitted by the International Committee on Veterinary Histological Nomenclature (ICVHN) to the World Association of Veterinary Anatomists Published on the website of the World Association of Veterinary Anatomists www.wava-amav.org 2017 CONTENTS Introduction i Principles of term construction in N.H.V. iii Cytologia – Cytology 1 Textus epithelialis – Epithelial tissue 10 Textus connectivus – Connective tissue 13 Sanguis et Lympha – Blood and Lymph 17 Textus muscularis – Muscle tissue 19 Textus nervosus – Nerve tissue 20 Splanchnologia – Viscera 23 Systema digestorium – Digestive system 24 Systema respiratorium – Respiratory system 32 Systema urinarium – Urinary system 35 Organa genitalia masculina – Male genital system 38 Organa genitalia feminina – Female genital system 42 Systema endocrinum – Endocrine system 45 Systema cardiovasculare et lymphaticum [Angiologia] – Cardiovascular and lymphatic system 47 Systema nervosum – Nervous system 52 Receptores sensorii et Organa sensuum – Sensory receptors and Sense organs 58 Integumentum – Integument 64 INTRODUCTION The preparations leading to the publication of the present first edition of the Nomina Histologica Veterinaria has a long history spanning more than 50 years. Under the auspices of the World Association of Veterinary Anatomists (W.A.V.A.), the International Committee on Veterinary Anatomical Nomenclature (I.C.V.A.N.) appointed in Giessen, 1965, a Subcommittee on Histology and Embryology which started a working relation with the Subcommittee on Histology of the former International Anatomical Nomenclature Committee. In Mexico City, 1971, this Subcommittee presented a document entitled Nomina Histologica Veterinaria: A Working Draft as a basis for the continued work of the newly-appointed Subcommittee on Histological Nomenclature. This resulted in the editing of the Nomina Histologica Veterinaria: A Working Draft II (Toulouse, 1974), followed by preparations for publication of a Nomina Histologica Veterinaria.
    [Show full text]
  • Tumor-Associated Stromal Cells As Key Contributors to the Tumor Microenvironment Karen M
    Bussard et al. Breast Cancer Research (2016) 18:84 DOI 10.1186/s13058-016-0740-2 REVIEW Open Access Tumor-associated stromal cells as key contributors to the tumor microenvironment Karen M. Bussard1,2, Lysette Mutkus3, Kristina Stumpf3, Candelaria Gomez-Manzano4 and Frank C. Marini1,3* Abstract The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.
    [Show full text]
  • The 4 Types of Tissues: Connective
    The 4 Types of Tissues: connective Connective Tissue General structure of CT cells are dispersed in a matrix matrix = a large amount of extracellular material produced by the CT cells and plays a major role in the functioning matrix component = ground substance often crisscrossed by protein fibers ground substance usually fluid, but it can also be mineralized and solid (bones) CTs = vast variety of forms, but typically 3 characteristic components: cells, large amounts of amorphous ground substance, and protein fibers. Connective Tissue GROUND SUBSTANCE In connective tissue, the ground substance is an amorphous gel-like substance surrounding the cells. In a tissue, cells are surrounded and supported by an extracellular matrix. Ground substance traditionally does not include fibers (collagen and elastic fibers), but does include all the other components of the extracellular matrix . The components of the ground substance vary depending on the tissue. Ground substance is primarily composed of water, glycosaminoglycans (most notably hyaluronan ), proteoglycans, and glycoproteins. Usually it is not visible on slides, because it is lost during the preparation process. Connective Tissue Functions of Connective Tissues Support and connect other tissues Protection (fibrous capsules and bones that protect delicate organs and, of course, the skeletal system). Transport of fluid, nutrients, waste, and chemical messengers is ensured by specialized fluid connective tissues, such as blood and lymph. Adipose cells store surplus energy in the form of fat and contribute to the thermal insulation of the body. Embryonic Connective Tissue All connective tissues derive from the mesodermal layer of the embryo . The first connective tissue to develop in the embryo is mesenchyme , the stem cell line from which all connective tissues are later derived.
    [Show full text]
  • Targeting Lymphotoxin Beta and Paired Box 5: a Potential
    Huang et al. Cancer Cell Int (2021) 21:3 https://doi.org/10.1186/s12935-020-01632-x Cancer Cell International PRIMARY RESEARCH Open Access Targeting Lymphotoxin Beta and Paired Box 5: a potential therapeutic strategy for soft tissue sarcoma metastasis Runzhi Huang1,2†, Zhiwei Zeng1†, Penghui Yan1†, Huabin Yin3, Xiaolong Zhu1, Peng Hu1, Juanwei Zhuang1, Jiaju Li1, Siqi Li4, Dianwen Song3*, Tong Meng2,3* and Zongqiang Huang1*† Abstract Background: Soft tissue sarcomas (STS) has a high rate of early metastasis. In this study, we aimed to uncover the potential metastasis mechanisms and related signaling pathways in STS with diferentially expressed genes and tumor-infltrating cells. Methods: RNA-sequencing (RNA-seq) of 261 STS samples downloaded from the Cancer Genome Atlas (TCGA) database were used to identify metastasis-related diferentially expressed immune genes and transcription factors (TFs), whose relationship was constructed by Pearson correlation analysis. Metastasis-related prediction model was established based on the most signifcant immune genes. CIBERSORT algorithm was performed to identify signifcant immune cells co-expressed with key immune genes. The GSVA and GSEA were performed to identify prognosis- related KEGG pathways. Ultimately, we used the Pearson correlation analysis to explore the relationship among immune genes, immune cells, and KEGG pathways. Additionally, key genes and regulatory mechanisms were vali- dated by single-cell RNA sequencing and ChIP sequencing data. Results: A total of 204 immune genes and 12 TFs, were identifed. The prediction model achieved a satisfactory efec- tiveness in distant metastasis with the Area Under Curve (AUC) of 0.808. LTB was signifcantly correlated with PAX5 (P < 0.001, R 0.829) and hematopoietic cell lineage pathway (P < 0.001, R 0.375).
    [Show full text]
  • Dual Role of TNF and Ltα in Carcinogenesis As Implicated by Studies in Mice
    cancers Review Dual Role of TNF and LTα in Carcinogenesis as Implicated by Studies in Mice Ekaterina O. Gubernatorova 1,2,*, Almina I. Polinova 1,2, Mikhail M. Petropavlovskiy 1,2, Olga A. Namakanova 1,2, Alexandra D. Medvedovskaya 1,2, Ruslan V. Zvartsev 1,3, Georgij B. Telegin 4, Marina S. Drutskaya 1,3,* and Sergei A. Nedospasov 1,2,3,5,* 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; [email protected] (A.I.P.); [email protected] (M.M.P.); [email protected] (O.A.N.); [email protected] (A.D.M.); [email protected] (R.V.Z.) 2 Department of Immunology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia 3 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 4 Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences (BIBCh, RAS), 142290 Pushchino, Russia; [email protected] 5 Sirius University of Science and Technology, Federal Territory Sirius, 354340 Krasnodarsky Krai, Russia * Correspondence: [email protected] (E.O.G.); [email protected] (M.S.D.); [email protected] (S.A.N.) Simple Summary: Tumor necrosis factor (TNF) and its closely related cytokine, lymphotoxin alpha (LTα), are part of the TNF superfamily and exert their functions via both overlapping and non- Citation: Gubernatorova, E.O.; redundant signaling pathways. Reported pro- and antitumorigenic effects of TNF and lymphotoxin Polinova, A.I.; Petropavlovskiy, M.M.; are often context-dependent and may be contingent on a particular experimental approach, such Namakanova, O.A.; Medvedovskaya, as transplantable and chemically induced tumor models; tissue and organ specificity; types of cells A.D.; Zvartsev, R.V.; Telegin, G.B.; producing these cytokines or responding to them; and the genotype and genetic background of mice.
    [Show full text]
  • Stroma: Fertile Soil for Inflammation', Best Practice & Research: Clinical Rheumatology, Vol
    University of Birmingham Stroma Patel, Rikesh; Filer, Andrew; Barone, Francesca; Buckley, Christopher D. DOI: 10.1016/j.berh.2014.10.022 License: Other (please specify with Rights Statement) Document Version Peer reviewed version Citation for published version (Harvard): Patel, R, Filer, A, Barone, F & Buckley, CD 2014, 'Stroma: fertile soil for inflammation', Best Practice & Research: Clinical Rheumatology, vol. 28, no. 4, pp. 565-576. https://doi.org/10.1016/j.berh.2014.10.022 Link to publication on Research at Birmingham portal Publisher Rights Statement: NOTICE: this is the author’s version of a work that was accepted for publication. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published as Patel R, Filer A, Barone F, Buckley CD, Stroma: Fertile soil for inflammation, Best Practice & Research Clinical Rheumatology (2014), doi: 10.1016/j.berh.2014.10.022. General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law. •Users may freely distribute the URL that is used to identify this publication. •Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research.
    [Show full text]