DOCSLIB.ORG

Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy Srustidhar Das1 and Surinder K

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy Srustidhar Das1 and Surinder K Published OnlineFirst November 2, 2015; DOI: 10.1158/0008-5472.CAN-15-1050 Cancer Review Research Understanding the Unique Attributes of MUC16 (CA125): Potential Implications in Targeted Therapy Srustidhar Das1 and Surinder K. Batra1,2,3 Abstract CA125, the most widely used ovarian cancer biomarker, was immunoadhesin HN125 to interfere MUC16 binding to mesothe- first identified approximately 35 years ago in an antibody screen lin. Since the identification of CA125 to be MUC16, it is hypoth- against ovarian cancer antigen. Two decades later, it was cloned esized to undergo proteolytic cleavage, a process that is considered and characterized to be a transmembrane mucin, MUC16. Since to be critical in determining the kinetics of MUC16 shedding as then, several studies have investigated its expression, functional, well as generation of a cell-associated carboxyl-terminal fragment and mechanistic involvement in multiple cancer types. Antibody- with potential oncogenic functions. In addition to our experi- based therapeutic approaches primarily using antibodies against mental demonstration of MUC16 cleavage, recent studies have the tandem repeat domains of MUC16 (e.g., oregovomab and demonstrated the functional importance of carboxyl terminal abagovomab) have been the modus operandi for MUC16-targeted fragments of MUC16 in multiple tumor types. Here, we provide therapy, but have met with very limited success. In addition, how our understanding of the basic biologic processes involving efforts have been also made to disrupt the functional cooperation MUC16 influences our approach toward MUC16-targeted thera- of MUC16 and its interacting partners; for example, use of a novel py. Cancer Res; 75(22); 1–6. Ó2015 AACR. Introduction of its cleavage (1, 6–8). Likewise, existence of splice forms without a transmembrane domain resulting in the secretory MUC16 is a type I transmembrane mucin that was cloned MUC16 has also been predicted (9). However, proper exper- and characterized independently by Lloyd and O'Brien in an imental validation is lacking to support these claims. Although effort toward biochemical characterization of CA125 (1–3). On 35 years have elapsed since the discovery of CA125 and 14 years the basis of the sequencing data, MUC16 is an extremely large since it was identified to be MUC16, our understanding of the glycoprotein (22,152 amino acids) with approximately 12,000 basic biologic processes involving MUC16 cleavage, promoter amino acids of the heavily O-glycosylated N-terminal region, a characterization, and therefore its regulation, existence of splice tandem repeat region comprising approximately 60 repeats of variants etc. is still rudimentary. Part of the problems in 156 amino acids each, a transmembrane domain and a cyto- addressing these issues lies with the enormous size and com- plasmic tail of 32 amino acids (Fig. 1A; ref. 4). MUC16 harbors plexity of this protein and lack of appropriate technical 56 SEA (sea urchin, enterokinase, and agrin) domains, the resources (such as antibodies for various regions of MUC16) highest among all mucins, and each SEA domain constitutes in addressing these problems. In this review, we focus on how a major portion (amino acids 1–128) of each tandem repeat our understanding of some of these basic processes (particu- (Fig. 1A, black outlined box at the bottom left; ref. 5). MUC16 larly cleavage) affects our outlook in exploiting the therapeutic is predicted to undergo cleavage in the penultimate and/or last potential of MUC16. SEA domain and phosphorylation event(s) in the cytoplasmic tail domain (CTD) is (are) believed to be critical determinants MUC16: A Historical Perspective In 1981, Bast and colleagues developed a monoclonal antibody 1 Department of Biochemistry and Molecular Biology, University of (i.e., OC125) that was reactive against epithelial ovarian cancer Nebraska Medical Center, Omaha, Nebraska. 2Department of Pathol- ogy, University of Nebraska Medical Center, Omaha, Nebraska. 3Buf- cells and cryopreserved tumor tissues from ovarian cancer fett Cancer Center, Eppley Institute for Research in Cancer and Allied patients, but not with the nonmalignant tissue samples (10). The Diseases, University of Nebraska Medical Center, Omaha, Nebraska. antigen that was reactive to this particular antibody was desig- Current address for S. Das: Department of Medicine, Karolinska Universitetss- nated as cancer antigen 125, hence the name CA125. Although jukhuset, Solna 171 76 Stockholm, Sweden. E-mail: [email protected] the antibody was developed with a therapeutic intent to treat the Corresponding Author: Surinder K. Batra, Department of Biochemistry and ovarian cancer patients, shedding of the antigen CA125 in to the Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, circulation did not bode well for that purpose. Instead, detection University of Nebraska Medical Center, 985870 Nebraska Medical Center, of the antigen CA125 in the circulation was foreseen as an Omaha, NE 68198-5870. Phone: 402-559-5455; Fax: 402-559-6650; E-mail: interesting opportunity to monitor the recurrent ovarian cancer [email protected] and still is the current gold standard marker for recurrent ovarian doi: 10.1158/0008-5472.CAN-15-1050 cancer. Although the potential of using CA125 toward (i) mon- Ó2015 American Association for Cancer Research. itoring the response to ovarian cancer treatment, (ii) recurrence of www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2015 American Association for Cancer Research. Das and Batra Published OnlineFirst November 2, 2015; DOI: 10.1158/0008-5472.CAN-15-1050 A Schematics of full-length MUC16 and a prototype tandem repeat N ? SEA = N SEA SEA SEA SEA55th SEA56th TM CTD C TR ANK1 ANK2 SEA DSVLV PLARRVDR TM PLTGNSDLPFWA Site # 2 Site # 1 Novel cleavage area “GSVVV” 12000 aa Tandem repeat (TR) Possible additional C 60+ repeats of 156 aa analogue cleavage site(s) of MUC1 Prototype TR of MUC16 Location of CA125 epitope reactive to OC125-mAb Actin CC CC ERM c-Src SEAn n=~10SEAn+1 n=~10 VTTRRRKKEGEYNVQQQCPGYYQSHLDLEDLQ ub ub P ub ub TRn TRn+1 nnub ub = N-Glycosylation site = O-Glycosylation site BCProposed model of proteolytic MUC16 interactome and possible processing of MUC16 therapeutic intervention NK cell ? CD16 higG1-Fc SEA SEA HN125 SEA NKG2D Siglec-9 sMUC16 SEA SEA SEA Full-length Hetero-dimeric Hetero-dimeric a d SEA TM IAB SEA MUC16-Cter TM b cell Mesothelial TM c a ~ ~ pH 5.0 Gal-3 pH 6.0 SEA SEA Gal-1 b TM SEA TM SEA SEA SEA SEA SEA Steric-hindrance TM TM TM SEA SEA SEA SEA SEA SEA Mesothelin TM SEA c TM TM Endothelium SEA Post-Golgi SEA SEA SEA SEA p38 P pH-7.0 Breflate ? TM SEA E-selectin CSC SEA trans TM Proliferation phenotype SEA TM MMP7 SEA d SEA SEA SEA pH-7.1 SEA TM Cyclin D1 LMO2 Golgi medial L-selectin Metastasis SEA NANOG Lymphocyte TM ER Apoptosis PP cis DR 5 STAT3 JAK2 TR 3 PP Meso JAK2 C-JUN Nucleus TM STAT3 SEA SEA Meso-TR3 e © 2015 American Association for Cancer Research OF2 Cancer Res; 75(22) November 15, 2015 Cancer Research Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst November 2, 2015; DOI: 10.1158/0008-5472.CAN-15-1050 MUC16 and Cancer Therapeutics the disease (ovarian cancer) following treatment, and/or (iii) mucins are hypothesized to be critical in mediating their sig- early detection of the disease was soon realized, its molecular naling functions and MUC16 (CA125) being one the most characterization took an overwhelmingly long two decades time widely used serum biomarker for ovarian cancer (23) and one till 2001, when Lloyd and O'Brien's groups independently dem- of the top three frequently mutated gene across many tumor onstrated that CA125 is indeed a very large membrane bound types (24), it is imperative to understand the cleavage of MUC16 mucin MUC16 (1–3). Since then, several groups, including ours, if we are to understand its role in tumorigenesis. One of the have attempted to characterize MUC16 with respect to its cleav- major hurdles in addressing MUC16 cleavage has been lack of age (11), trafficking (12), regulation of expression (13, 14), and antibodies for the C-terminal region as most of the well-char- its functional involvement in health and disease (15–21). Recent- acterized antibodies bind to the repetitive epitopes (i.e., CA125) ly, Cheon and colleagues generated and characterized a whole in the tandem repeat region. To circumvent the lack of anti- body Muc16 knockout mouse model (22). These mice are viable bodies for the C-terminal MUC16, we used dual epitope tagging and fertile with lack of any apparent developmental defects (22) of various lengths of carboxyl-terminal MUC16 fragments to and therefore, can be used as an interesting tool to address the narrow down the potential site of cleavage. We observed that basic questions related to Muc16/MUC16. earlier predicted sites #1 and #2 are not essential for MUC16 cleavage, instead a novel stretch of 12 amino acids in the juxta- membrane ectodomain (PLTGNSDLPFWA) was found to be MUC16 Cleavage: A Long-Standing Question sufficient for MUC16 cleavage (Fig. 1A; ref. 11). Although this Because the molecular identity of CA125 was revealed to be a novel stretch of 12 amino acids was found to be sufficient for single pass transmembrane mucin MUC16 (2, 3), predictions MUC16 cleavage, it is not an absolute necessity, as deletion of have been made about its possible cleavage in the juxta-mem- this stretch did not result in complete abrogation of MUC16 brane SEA domains. Primarily, the PLARRVDR site (site #1) in cleavage (11). It can thus be speculated that MUC16 cleavage the last (56th; ref. 1) and DSVLV site (site #2, analogous to may not be entirely dependent on its primary amino acid GSVVV site on MUC1) on the penultimate (55th; ref.
Load more

Recommended publications
  • Early Acute Microvascular Kidney Transplant Rejection in The
    CLINICAL RESEARCH www.jasn.org Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens Marianne Delville,1,2,3 Baptiste Lamarthée,4 Sylvain Pagie,5,6 Sarah B. See ,7 Marion Rabant,3,8 Carole Burger,3 Philippe Gatault ,9,10 Magali Giral,11 Olivier Thaunat,12,13,14 Nadia Arzouk,15 Alexandre Hertig,16,17 Marc Hazzan,18,19,20 Marie Matignon,21,22,23 Christophe Mariat,24,25 Sophie Caillard,26,27 Nassim Kamar,28,29 Johnny Sayegh,30,31 Pierre-François Westeel,32 Cyril Garrouste,33 Marc Ladrière,34 Vincent Vuiblet,35 Joseph Rivalan,36 Pierre Merville,37,38,39 Dominique Bertrand,40 Alain Le Moine,41,42 Jean Paul Duong Van Huyen,3,8 Anne Cesbron,43 Nicolas Cagnard,3,44 Olivier Alibeu,3,45 Simon C. Satchell,46 Christophe Legendre,3,4,47 Emmanuel Zorn,7 Jean-Luc Taupin,48,49,50 Béatrice Charreau,5,6 and Dany Anglicheau 3,4,47 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allo- grafts, non-anti–HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed. Methods We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR).
    [Show full text]
  • Incidental Finding of Raised CA125
    Case Report iMedPub Journals Critical Care Obstetrics and Gynecology 2019 http://www.imedpub.com/ Vol.5 No.1:3 ISSN 2471-9803 DOI: 10.21767/2471-9803.1000170 Incidental Finding of Raised CA125: a Cause for Concern? Farshad Tahmasebi1*, Rahul Nath1, Nava Sokolovsky1, Johannah Scaffidi1, Jane Boley1, Gautam Mehra1 and Ahmad Sayanseh1,2 1Department of Gynaecological Oncology, St Thomas’ Hospital, London, UK 2School of Life Course Sciences, King’s College London, Guy’s, Kings College and St. Thomas’ Hospital, London, UK, School of Medical Education, King’s College, London, UK *Corresponding author: Farshad Tahmasebi, Department of Gynaecological Oncology, St Thomas’ Hospital, London, UK, E-mail: [email protected] Received date: October 30, 2018; Accepted date: November 15, 2018; Published date: November 21, 2018 Copyright: © 2018 Tahmasebi F, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Tahmasebi F, Nath R, Sokolovsky N, Scaffidi J, Boley J, et al. (2018) Incidental Finding of Raised CA125: a Cause for Concern? Crit Care Obst Gyne Vol.5 No.1:3. Although much research has been done to understand the molecular structure of CA 125, its functions remain a source of Abstract much speculation. It is expressed in tissues derived from embryonic coelomic epithelium such as endometrium, Mullerian Cancer antigen 125 (also known as carbohydrate antigen epithelium, peritoneum, pleura and pericardium [4]. Within 125 or CA 125) is an antigen first identified by Bast et al.
    [Show full text]
  • TACI:Fc Scavenging B Cell Activating Factor (BAFF) Alleviates Ovalbumin-Induced Bronchial Asthma in Mice
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 39, No. 3, 343-352, June 2007 TACI:Fc scavenging B cell activating factor (BAFF) alleviates ovalbumin-induced bronchial asthma in mice 1,2,3 2 Eun-Yi Moon and Sook-Kyung Ryu the percentage of non-lymphoid cells and no changes were detected in lymphoid cell population. 1 Department of Bioscience and Biotechnology Hypodiploid cell formation in BALF was decreased Sejong University by OVA-challenge but it was recovered by TACI:Fc Seoul 143-747, Korea treatment. Collectively, data suggest that asthmatic 2 Laboratory of Human Genomics symptom could be alleviated by scavenging BAFF Korea Research Institute of Bioscience and Biotechnology (KRIBB) and then BAFF could be a novel target for the Daejeon 305-806, Korea develpoment of anti-asthmatic agents. 3 Corresponding author: Tel, 82-2-3408-3768; Fax, 82-2-466-8768; E-mail, [email protected] Keywords: asthma; B-cell activating factor; ovalbu- and [email protected] min; transmembrane activator and CAML interactor protein Accepted 28 March 2007 Introduction Abbreviations: BAFF, B cell activating factor belonging to TNF- family; BALF, bronchoalveolar lavage fluid; OVA, ovalbumin; PAS, Mature B cell generation and maintenance are regu- periodic acid-Schiff; Prx, peroxiredoxin; TACI, transmembrane lated by B-cell activating factor (BAFF). BAFF is pro- activator and calcium modulator and cyclophilin ligand interactor duced by macrophages or dendritic cells upon stim- ulation with LPS or IFN- . BAFF belongs to the TNF family. Its biological role is mediated by the specific Abstract receptors, B-cell maturation antigen (BCMA), trans- membrane activator and calcium modulator and cy- Asthma was induced by the sensitization and chal- clophilin ligand interactor (TACI) and BAFF receptor, lenge with ovalbumin (OVA) in mice.
    [Show full text]
  • Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis
    International Journal of Molecular Sciences Review Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis Aldona Kasprzak 1,* and Agnieszka Adamek 2 1 Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecicki Street 6, 60-781 Pozna´n,Poland 2 Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Szwajcarska Street 3, 61-285 Pozna´n,Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-61-8546441; Fax: +48-61-8546440 Received: 25 February 2019; Accepted: 10 March 2019; Published: 14 March 2019 Abstract: Mucins are large O-glycoproteins with high carbohydrate content and marked diversity in both the apoprotein and the oligosaccharide moieties. All three mucin types, trans-membrane (e.g., MUC1, MUC4, MUC16), secreted (gel-forming) (e.g., MUC2, MUC5AC, MUC6) and soluble (non-gel-forming) (e.g., MUC7, MUC8, MUC9, MUC20), are critical in maintaining cellular functions, particularly those of epithelial surfaces. Their aberrant expression and/or altered subcellular localization is a factor of tumour growth and apoptosis induced by oxidative stress and several anti-cancer agents. Abnormal expression of mucins was observed in human carcinomas that arise in various gastrointestinal organs. It was widely believed that hepatocellular carcinoma (HCC) does not produce mucins, whereas cholangiocarcinoma (CC) or combined HCC-CC may produce these glycoproteins. However, a growing number of reports shows that mucins can be produced by HCC cells that do not exhibit or are yet to undergo, morphological differentiation to biliary phenotypes. Evaluation of mucin expression levels in precursors and early lesions of CC, as well as other types of primary liver cancer (PLC), conducted in in vitro and in vivo models, allowed to discover the mechanisms of their action, as well as their participation in the most important signalling pathways of liver cystogenesis and carcinogenesis.
    [Show full text]
  • MUC16 (CA125): Tumor Biomarker to Cancer Therapy, a Work in Progress
    Felder et al. Molecular Cancer 2014, 13:129 http://www.molecular-cancer.com/content/13/1/129 REVIEW Open Access MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress Mildred Felder1†, Arvinder Kapur1†, Jesus Gonzalez-Bosquet2, Sachi Horibata1, Joseph Heintz3, Ralph Albrecht3, Lucas Fass1, Justanjyot Kaur1, Kevin Hu4, Hadi Shojaei1, Rebecca J Whelan4* and Manish S Patankar1* Abstract Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a3–5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin.
    [Show full text]
  • Inhibitory Effects of Activin on the Growth and Morphogenesis of Primary and Transformed Mammary Epithelial Cells'
    ICANCERRESEARCH56. I 155-I 163. March I. 19961 Inhibitory Effects of Activin on the Growth and Morphogenesis of Primary and Transformed Mammary Epithelial Cells' Qiu Yan Liu, Birunthi Niranjan, Peter Gomes, Jennifer J. Gomm, Derek Davies, R. Charles Coombes, and Lakjaya Buluwela2 Departments of Medical Oncology (Q. Y. L, P. G.. J. J. G., R. C. C., L B.J and Biochemistry (Q. Y. L. L B.J. Charing Cross and Westminster Medical School, Fuiham Palace Road. London W6 8RF; Division of Cell Biology and Experimental Pathology. Institute of Cancer Research, 15 Cotswald Rood, Sutton. Surrey SM2 SNG (B. NJ; and FACS Analysis Laboratory. imperial Cancer Research Fund, Lincoln ‘sInnFields. London WC2A 3PX (D. DI, United Kingdom ABSTRACT logical activities of activin. Indeed, two types of activin receptors have aLready been identified in the mouse (28) and several forms in Activin Is a member of the transforming growth factor fi superfamily, Xenopus (29, 30). The sequences of the Act-RI! (3 1), the TGF-@ type which is known to have activities Involved In regulating differentiation II receptor (32), the TGF-f3 type I receptor (33), and various activin and development. By using reverse transcrlption.PCR analysis on immu noafflnity.purlfied human breast cells, we have found that activin IJa and receptor-like genes (34) have been described. The comparison of these activin type II receptor are expressed by myoepithelial cells, whereas no sequences shows that they belong to a newly defined family of expression was detected In other breast cell types. In examining 15 breast membrane-bound, ligand-activated serine-threonine kinases (35).
    [Show full text]
  • Proteins That Interact with the Mucin-Type Glycoprotein Msb2p
    bioRxiv preprint doi: https://doi.org/10.1101/786475; this version posted September 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Msb2p Interacting Proteins Prabhakar et al. Proteins That Interact with the Mucin-Type Glycoprotein Msb2p Include Regulators of the Actin Cytoskeleton by Aditi Prabhakar, Nadia Vadaie, Thomas Krzystek, and Paul J. Cullen† Department of Biological Sciences at SUNY-Buffalo, 14260-1300 Running title: Msb2p interacting proteins Key Words: protein microarray, mucin, MAP kinase, actin cytoskeleton, Msb2p, actin capping, secretion, glutamine synthetase. † Corresponding author: Paul J. Cullen Address: Department of Biological Sciences 532 Cooke Hall State University of New York at Buffalo Buffalo, NY 14260-1300 Phone: (716)-645-4923 FAX: (716)-645-2975 e-mail: [email protected] 36 pages, 8 Figures, 3 Tables, , 1 Supplemental Table; 50,465 characters 1 bioRxiv preprint doi: https://doi.org/10.1101/786475; this version posted September 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Msb2p Interacting Proteins Prabhakar et al. ABSTRACT Transmembrane mucin-type glycoproteins can regulate signal transduction pathways. In yeast, signaling mucins regulate mitogen-activated protein kinase (MAPK) pathways that induce cell differentiation to filamentous growth (fMAPK pathway) and the response to osmotic stress (HOG pathway). To explore regulatory aspects of signaling mucin function, protein microarrays were used to identify proteins that interact with the cytoplasmic domain of the mucin-like glycoprotein, Msb2p.
    [Show full text]
  • Inhibin A, B and Pro-Ac in Serum and Peritoneal Fluid in Postmenopausal Patients with Ovarian Tumors
    European Journal of Endocrinology (2000) 142 334–339 ISSN 0804-4643 CLINICAL STUDY Inhibin A, B and pro-aC in serum and peritoneal fluid in postmenopausal patients with ovarian tumors Sirkka-Liisa Ala-Fossi1, Juhani Ma¨enpa¨a¨1, Merja Bla¨uer2, Pentti Tuohimaa2 and Reijo Punnonen1,3 1Department of Obstetrics and Gynecology, Tampere University Hospital, 2Department of Anatomy and 3 Medical School, University of Tampere, Tampere, Finland (Correspondence should be addressed to S-L Ala-Fossi, Department of Obstetrics and Gynecology, Tampere University Hospital, PO Box 2000, FIN- 33521 Tampere, Finland; Email: sirkka-liisa.ala-fossi@uta.fi) Abstract Objective: To compare serum and peritoneal fluid concentrations of inhibin A, B, and pro-aC in women with ovarian tumors. Methods: Serum and peritoneal fluid samples were taken from 41 postmenopausal women operated on for an ovarian tumor. Twenty-one patients with endometrial cancer formed a control group. Serum and peritoneal fluid inhibin A, B, and pro-aC concentrations, and serum FSH and tumor marker CA 125 (study group only) concentrations were analyzed. Results: Inhibin A was found in low concentrations (median 4.1 pg/ml, range < 2–29 pg/ml) in serum in most postmenopausal patients with epithelial ovarian carcinoma, whereas inhibin B was not measurable. Inhibin pro-aC circulated in high concentrations (median 125 pg/ml, range 37- >1000 pg/ml). All inhibins were found in clearly greater concentrations in the peritoneal fluid than in serum. International Federation of Gynecology and Obstetrics (FIGO) stage III-IV and poor differentiation grade were associated with significantly lower concentrations of inhibin A and pro- aC in the peritoneal fluid compared with stages I-II or low grade.
    [Show full text]
  • Interactions of Mucins with Biopolymers and Drug Delivery Particles
    INTERACTIONS OF MUCINS WITH BIOPOLYMERS AND DRUG DELIVERY PARTICLES Malmö University Health and Society Doctoral Dissertations 2008:2 © Olof Svensson 2008 ISBN 978-91-7104-212-5 ISSN 1653-5383 Holmbergs, Malmö 2008 OLOF SVENSSON INTERACTIONS OF MUCINS WITH BIOPOLYMERS AND DRUG DELIVERY PARTICLES Malmö University, 2008 The Faculty of Health and Society To my family CONTENTS ABSTRACT ................................................................................ 10 LIST OF PAPERS ......................................................................... 12 INTRODUCTION ......................................................................... 14 Background and aim ............................................................................ 14 The mucous gel and mucins ................................................................... 16 Polyelectrolyte multilayers ...................................................................... 22 MATERIALS AND METHODS ......................................................... 27 Proteins and polymers ............................................................................ 27 Surfaces .............................................................................................. 30 Ellipsometry ......................................................................................... 31 Particle electrophoresis ........................................................................... 40 Atomic force microscopy ........................................................................ 41 Electrochemistry
    [Show full text]
  • Modulation of MUC1 Mucin As an Escape Mechanism of Breast Cancer Cells from Autologous Cytotoxic T-Lymphocytes
    British Journal of Cancer (2001) 84(9), 1258–1264 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1744, available online at http://www.idealibrary.com on http://www.bjcancer.com Modulation of MUC1 mucin as an escape mechanism of breast cancer cells from autologous cytotoxic T-lymphocytes K Kontani1, O Taguchi1, T Narita1, M Izawa1, N Hiraiwa1, K Zenita1, T Takeuchi2, H Murai2, S Miura2 and R Kannagi1 1Program of Molecular Pathology and 2Department of Breast Surgery, Aichi Cancer Center, 1–1 Kanokoden, Chikusa-ku, Nagoya 464–8681, Japan Summary MUC1 mucin is known to serve as a target molecule in the killing of breast cancer cells by cytotoxic T-lymphocytes (CTLs). We searched for a possible mechanism allowing tumour cells to escape from autologous CTLs. When the killing of breast cancer cells by autologous lymphocytes was examined in 26 patients with breast cancer, significant tumour cell lysis was observed in 8 patients, whereas virtually no autologous tumour cell lysis was detected in as many as 18 patients. In the patients who showed negligible tumour cell lysis, the autologous tumour cells expressed MUC1-related antigenic epitopes much more weakly than the tumour cells in the patients who exhibited strong cytotoxicity (significant statistically at P < 0.0005–0.0045), suggesting that the unresponsiveness of cancer cells to CTLs observed in these patients was mainly due to loss of MUC1 expression or modulation of its antigenicity. A breast cancer cell line, NZK-1, established from one of the cytotoxicity- negative patients, did not express MUC1 and was resistant to killing by CTLs, while control breast cancer cell lines expressing MUC-1 were readily killed by CTLs.
    [Show full text]
  • Mucin-Selective Protease Stce Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins
    The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins Stacy A. Malakera,1, Kayvon Pedrama,1, Michael J. Ferracaneb, Barbara A. Bensingc, Venkatesh Krishnand, Christian Pette,f, Jin Yue, Elliot C. Woodsa, Jessica R. Kramerg, Ulrika Westerlinde,f, Oliver Dorigod, and Carolyn R. Bertozzia,h,2 aDepartment of Chemistry, Stanford University, Stanford, CA 94305; bDepartment of Chemistry, University of Redlands, Redlands, CA 92373; cDepartment of Medicine, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA 94143; dStanford Women’s Cancer Center, Division of Gynecologic Oncology, Stanford University, Stanford, CA 94305; eLeibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany; fDepartment of Chemistry, Umeå University, 901 87 Umeå, Sweden; gDepartment of Bioengineering, University of Utah, Salt Lake City, UT 84112; and hHoward Hughes Medical Institute, Stanford, CA 94305 Edited by Laura L. Kiessling, Massachusetts Institute of Technology, Cambridge, MA, and approved February 25, 2019 (received for review July 30, 2018) Mucin domains are densely O-glycosylated modular protein domains When strung together in “tandem repeats” mucin domains can that are found in a wide variety of cell surface and secreted proteins. form the large structures characteristic of mucin family proteins. Mucin-domain glycoproteins are known to be key players in a host Mucins can be hundreds to thousands of amino acids long of human diseases, especially cancer, wherein mucin expression and and >50% glycosylation by mass (11); MUC16, one of the largest glycosylation patterns are altered. Mucin biology has been difficult mucins, can exceed 22,000 residues and 85% glycosylation by mass to study at the molecular level, in part, because methods to manip- (12), with a persistence length of 1–5 μm (13).
    [Show full text]
  • Mucin Dynamics and Enteric Pathogens
    FOCUS ON MUCOSAL MICROBIOLOGYREVIEWS Mucin dynamics and enteric pathogens Michael A. McGuckin*, Sara K. Lindén‡, Philip Sutton§ and Timothy H. Florin* Abstract | The extracellular secreted mucus and the cell surface glycocalyx prevent infection by the vast numbers of microorganisms that live in the healthy gut. Mucin glycoproteins are the major component of these barriers. In this Review, we describe the components of the secreted and cell surface mucosal barriers and the evidence that they form an effective barricade against potential pathogens. However, successful enteric pathogens have evolved strategies to circumvent these barriers. We discuss the interactions between enteric pathogens and mucins, and the mechanisms that these pathogens use to disrupt and avoid mucosal barriers. In addition, we describe dynamic alterations in the mucin barrier that are driven by host innate and adaptive immune responses to infection. Commensal microorganism An enormous surface area of mucosal epithelial cells in consists of a single layer of columnar epithelial cells A microorganism living in a the gastrointestinal tract is potentially exposed to enteric covered by a layer of secreted mucus that is at its thick­ mutually advantageous microorganisms. The mucosal epithelium has highly est in the stomach and colon. This is the major barrier relationship with a mammalian specialized functions throughout the gastrointestinal separating the epithelial cells and underlying host tissues host (for example, in the lumen tract to allow ingested food to be digested,
    [Show full text]