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Aus Der Medizinischen Klinik Und Poliklinik IV Der Ludwig-Maximilians-Universität München Arbeitsgruppe Klinische Biochemie Vorstand: (Direktor: Prof

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Aus Der Medizinischen Klinik Und Poliklinik IV Der Ludwig-Maximilians-Universität München Arbeitsgruppe Klinische Biochemie Vorstand: (Direktor: Prof Aus der Medizinischen Klinik und Poliklinik IV der Ludwig-Maximilians-Universität München Arbeitsgruppe Klinische Biochemie Vorstand: (Direktor: Prof. Dr. med. Martin Reincke) Characterization and Targeted Therapy of Stem Cell-Like Side Population Cells in Pancreatic Cancer and Esophageal Cancer Dissertation zum Erwerb des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Yue Zhao Aus Jiang Su, China 2013 Mit der Genehmigung der medizinischen Fakultät der Universität München Erstgutachter: Prof. Dr. Peter J. Nelson Zweitgutachter: Priv. Doz. Dr. Peter Neth Mitbetreuung durch den promovierten Mitarbeiter: Prof. Dr. med. Christiane J. Bruns Dekan: Prof. Dr. med. Dr. h.c. Maximilian Reiser, FACR, FRCR Tag der mündlichen Prüfung: 12.09.2013 1 Das Projekt wurde gefördert durch die vorliegende Arbeit unter Anleitung von Prof. Dr. med. Christiane J. Bruns im Forschungslabor der chirurgischen Klinik und Poliklinik Großhadern und Prof. Dr. Peter J. Nelson in der Arbeitsgruppe Klinischen Biochemie der Ludwig- Maximilians-Universität München durchgeführt. Das Projekt wurde gefördert durch die Deutsche Krebshilfe Nr: 108168 von Prof. Dr. med. Christiane J. Bruns und die DFG SPP1190 ‘Tumor Vessel Interface’ von Prof. Dr. med. Christiane J. Bruns sowie Prof. Dr. Peter J. Nelson. 2 Declaration I hereby declare that the thesis is my original work. The work and results presented in the thesis were performed independently. Part of the in vitro target therapy data in pancreatic cancer cell lines was generated in cooperation with Dr. Peter Camaj and Dr. Ivan Ischenko. The side population analysis on LSR II FACs machine was performed by technical support from Dr. Myslliwitz (Helmholtz center, Munich, Germany). Dr. Ellwart helped to carry out the isolation of side population cells with the Moflo flow cytometer (Helmholtz center, Munich, Germany). Parts of the results have been included in the following manuscripts: 1. Antisense inhibition of microRNA-21 and -221 in tumor-initiating stem-like cells modulates biological functions of pancreatic cancer including tumorigenesis, metastasis, and chemoresistance 2. Characterization of stem cell-like side populations in esophageal cancer: a potential source of chemotherapy resistance and metastases. Stem Cells Dev. 2013 Sep 10. Epub ahead of print. No unauthorized data were included. Information from the literature was cited and listed in the reference. All the data presented in the thesis will not be used in any other thesis for scientific degree application. The work for the thesis began from September 2010 with the supervision from Prof. Dr. Peter J. Nelson and Prof. Dr. med. Christiane J. Bruns in Ludwig-Maximilians University Munich, Germany. 09.2013, München Yue Zhao 3 Um Krankheiten zu behandeln und zu heilen, muss man nach ihren Ursprüngen suchen. - Buch des Gelben Kaisers zur Inneren Medizin1 治病必求於本 - 黄帝内经 1 Ubersetzt aus: Muhammad W Schmidt, 2004, Der klassiker des gelben Kaisers zur Inneren Medizin, viademica.verlag, Berlin 4 TABLE OF CONTENTS TABLE OF CONTENTS I. ABSTRACT ................................................................................................................................... 1 1.1 Pancreatic cancer ............................................................................................................................ 1 1.2 Esophageal cancer .......................................................................................................................... 3 II. INTRODUCTION ....................................................................................................................... 4 2.1 Pancreatic cancer ............................................................................................................................ 4 2.1.1 Background of pancreatic cancer ....................................................................................................... 4 2.1.2 Management of pancreatic cancer ..................................................................................................... 4 2.1.3 Gemcitabine induced chemoresistance in pancreatic cancer ................................................ 5 2.1.4 The biology of pancreatic cancer ........................................................................................................ 6 2.1.5 Cancer stem cells in pancreatic cancer ............................................................................................ 7 2.1.6 miRNAs in pancreatic cancer ............................................................................................................... 8 2.1.7 miRNAs regulated cancer stem cells ................................................................................................. 9 2.1.8 miRNA-based therapeutics ................................................................................................................ 10 2.1.9 Aim of the study ...................................................................................................................................... 11 2.2 Esophageal cancer ....................................................................................................................... 12 2.2.1 Background of esophageal cancer .................................................................................................. 12 2.2.2 Management of esophageal cancer ................................................................................................. 13 2.2.3 Chemotherapy and chemoresistance in esophageal cancer ................................................ 14 2.2.4 The biology of esophageal cancer ................................................................................................... 15 2.2.5 Cancer stem cells in esophageal cancer (side population model) .................................... 18 2.2.6 Aspirin as Wnt signaling inhibitor in esophageal cancer ...................................................... 19 2.2.7 Aim of the study ...................................................................................................................................... 19 III. MATERIAL AND METHODS .............................................................................................. 20 3.1 Materials ......................................................................................................................................... 20 3.1.1 Cell lines ..................................................................................................................................................... 20 3.1.2 Reagents ..................................................................................................................................................... 22 3.1.3 Technical equipements ........................................................................................................................ 22 3.1.4 Cell culture materials ............................................................................................................................ 23 3.1.5 Cell culture and frozen medium ....................................................................................................... 24 3.1.6 Materials for cell proliferation and cytotoxity assay .............................................................. 25 3.1.7 Materials for transfection and real time PCR ............................................................................. 25 3.1.1 Materials for western blot, flow cytometry, Immunofluorescence, and immunohistochemistry ....................................................................................................................................... 26 I TABLE OF CONTENTS 3.1.2 Materials for animal experiments ................................................................................................... 28 3.1.1 Software ..................................................................................................................................................... 28 3.2 Methods ........................................................................................................................................... 29 3.2.1 Methods of pancreatic cancer ........................................................................................................... 29 3.2.2 Methods of esophageal cancer .......................................................................................................... 33 3.3 Experimental setting .................................................................................................................. 37 3.3.1 Pancreatic cancer ................................................................................................................................... 37 3.3.2 Esophageal cancer ................................................................................................................................. 39 IV. RESULTS ................................................................................................................................. 40 4.1 Cancer stem cell target therapy in pancreatic cancer ..................................................... 40 4.1.1 Microarray data Validation ................................................................................................................. 40 4.1.2 miR-21 and -221 antisense therapies in vitro ............................................................................ 42 4.1.3 Overexpression of miR-21 and -221 in
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