UvA-DARE (Digital Academic Repository) What tumor cells cannot resist Ebbing, E.A. Link to publication Citation for published version (APA): Ebbing, E. A. (2018). What tumor cells cannot resist: Mechanisms of therapy resistance in esophageal adenocarcinoma General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl) Download date: 02 Jan 2019
WHAT TUMOR CELLS CANNOT RESIST: MECHANISMS OF THERAPY RESISTANCE IN ESOPHAGEAL ADENOCARCINOMA Eva A. Ebbing
The research described in this thesis was performed at the Center for Experimental and Molecular Medicine (CEMM), Laboratory for Experimental Oncology and Radiobiology (LEXOR) and the Department of Medical Oncology at the Academic Medical Center (AMC), University of Amsterdam (UvA), The Netherlands. About the cover The cover shows three elements of an electronic circuit all ending in the same resistor, which represents the epithelial to mesenchymal transition as the identified mechanism of resistance either induced upon therapeutic pressure or by a tumor stroma related component. The capacitor and inductor (upper component) illustrates growth factor receptor targeted therapy. The middle component, the transistor, depicts chemoradiation therapy. Cancer associated fibroblasts-secreted IL-6 is represented by the lower compartment, the diode. Cover design: Bregje Jaspers, Eva A. Ebbing and Rob W. Robert Lay-out: RON Graphic Power, www.ron.nu Printing: ProefschriftMaken www.proefschriftmaken.nl ISBN: 978-94-6295-873-9 Copyright 2018 by E.A. Ebbing. All rights reserved. No part of this thesis may be reproduced in any form or by any means without prior permission of the author.
WHAT TUMOR CELLS CANNOT RESIST: MECHANISMS OF THERAPY RESISTANCE IN ESOPHAGEAL ADENOCARCINOMA ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. K.I.J. Maex ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 6 april 2018, te 14:00 uur door Eva Adinda Ebbing geboren te Graft-De Rijp
Promotiecommissie: Promotor(es): prof. dr. H.W.M. van Laarhoven AMC-UvA prof. dr. J.P. Medema AMC-UvA Copromotor(es): dr. M.F. Bijlsma prof. dr. C.J.A. Punt AMC-UvA AMC-UvA Overige leden: prof. dr. H.I. Grabsch Maastricht University prof. dr. R.P. Coppes Rijksuniversiteit Groningen dr. L.M.A. Ritsma Universiteit Leiden prof. dr. E. Dekker AMC-UvA prof. dr. C.J.F. van Noorden AMC-UvA prof. dr. L. Vermeulen AMC-UvA Faculteit der Geneeskunde
Table of contents Chapter 1 General introduction and outline of the thesis 7 Chapter 2 A systematic review and meta-analysis of prognostic biomarkers in resectable esophageal adenocarcinoma 17 Chapter 3 The dynamics of HER2 status in esophageal adenocarcinoma 47 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Establishment of patient-derived xenograft models and cell lines for malignancies of the upper gastrointestinal tract 65 ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3 85 Esophageal Adenocarcinoma Cells and Xenograft Tumors Exposed to Erb-b2 Receptor Tyrosine Kinase 2 and 3 Inhibitors Activate Transforming Growth Factor Beta Signaling, Which Induces Epithelial to Mesenchymal Transition 105 Chemoradiation induces epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma 143 Stromal derived interleukin-6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma 159 Chapter 9 General discussion and Future perspectives 189 Annexes English Summary 202 Nederlandse Samenvatting 205 Curriculum Vitae 209 PhD Portfolio 210 List of Publications 211 Dankwoord 213