Verfügbarkeit: The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer

The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer:

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Bibliographische Detailangaben
Beteilige Person:	Freire Valls, Aida (VerfasserIn)
Format:	Hochschulschrift/Dissertation Buch
Sprache:	Englisch
Veröffentlicht:	Heidelberg [2018]
Schlagwörter:	Hochschulschrift
Links:	http://d-nb.info/1171582099/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030870493&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
Umfang:	137 Seiten Illustrationen, Diagramme 30 cm

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Datensatz im Suchindex

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adam_text	TABLE OF CONTENTS SUMMARY............................................................................................................................... XI ZUSAMMENFASSUNG............................................................................................................ XIII LIST OF ABBREVIATIONS.......................................................................................................... XV LIST OF FIGURES.................................................................................................................... XVII LIST OF TABLES...................................................................................................................... XIX 1. INTRODUCTION............................................................................................................. 21 1.1. COLORECTAL CANCER............................................................................................. 21 1.1.1. DEVELOPMENT OF CRC PRIMARY TUMOR ....................................................... 21 1.1.2. DEVELOPMENT OF LIVER METASTASIS ............................................................. 23 1.1.2.1. HISTOLOGIC GROWTH PATTERNS OF LIVER METASTASIS..................................................25 1.2. PROSECUTING THE MICROENVIRONMENT FOR LEADING TUMOR METASTASIS.... 26 1.2.1. MACROPHAGES: THEIR ROLE IN ANGIOGENESIS AND IN MEDIATING ANTI-ANGIOGENIC THERAPY RESISTANCE....................................................................................................28 1.2.2. MACROPHAGE ACTIVATION - THE M L AND M2 PHENOTYPE .............................. 29 1.2.2.1. MACROPHAGE ONTOGENY.........................................................................................31 1.2.2.2. THE PLEIOTROPIC ROLES OF IL-10...............................................................................32 1.3. REGULATION OF TUMOR ANGIOGENESIS - FOCUS ON MACROPHAGES ................ 33 1.3.1. VEGFR1.................................................................................................... 34 1.3.2. LRG1......................................................................................................... 36 1.4. MACROPHAGES AND VESSEL DENSITY IN CRC, A CLINICAL PERSPECTIVE..........38 1.4.1. INFLUENCE OF MACROPHAGES ON PATIENT OUTCOME.......................................38 1.4.2. INFLUENCE OF VESSEL DENSITY ON PATIENT OUTCOME ...................................... 40 1.5. THE PROGNOSTIC VALUE OF VEGFR1 AND LRG1 IN CANCER ............................ 41 1.5.1. VEGFR1.................................................................................................... 41 1.5.2. LRG1....................................................................................... 42 2. AIMS OF THE DISSERTATION.........................................................................................43 3. RESULTS......................................................................................................................45 3.1. ESTABLISHMENT OF A CLINICALLY RELEVANT MOUSE MODEL OF CRLM ................. 45 3.1.1. SIMILAR MACROPHAGE INFILTRATION BUT DIFFERENT VASCULAR PATTERNS IN PRIMARY TUMORS AND LIVER METASTASIS OF CRC........................................................................ 45 3.1.2. SIMILAR IMMUNE INFILTRATION WITHIN CRC PRIMARY TUMORS AND LIVER METASTASIS.................................................................................................................47 3.2. MACROPHAGES CHANGE THEIR GENE EXPRESSION DEPENDING ON THE TUMOR MICROENVIRONMENT...................................................................................................... 48 3.2.1. MAMS ARE SKEWED TOWARDS AN M2 PRO-ANGIOGENIC PHENOTYPE .............. 50 3.3. VEGFR1* MAMS CONTRIBUTE TO METASTATIC ANGIOGENESIS AND INFLUENCE PATIENT OUTCOME...........................................................................................................52 3.3.1. FLT1+ MAMS INDUCE SPROUTING ANGIOGENESIS ............................................ 53 3.3.2. MYELOID CELLS FROM HUMAN MCRC ARE VEGFR1+ AND ANGIOGENIC ... 54 3.3.3. VEGFR1+ CELLS IN LM ASSOCIATE WITH VESSEL DENSITY AND WORST CLINICAL OUTCOME ................................................................................................................... 56 3.3.4. CIRCULATING VEGFR1+ MACROPHAGES PREDICT DISEASE RECURRENCE IN METASTATIC PATIENTS.................................................................................................... 61 3.3.5. CIRCULATING VEGFRV MACROPHAGES PREDICT SITE OF DISEASE RECURRENCE IN METASTATIC PATIENTS.................................................................................................... 64 3.4. MAMS HAVE A UNIQUE PRO-ANGIOGENIC SIGNATURE ........................................ 65 3.4.1. LRG1 IS SPECIFICALLY EXPRESSED BY MAMS............................................65 3.4.2. IL-10-STAT3 MEDIATED LRG1 UPREGULATION IN MAMS ......................... 67 3.4.3. LRG1 FROM MAMS CAN ACTIVATE ENDOTHELIAL CELLS ............................. 69 3.5. DEPLETION OF MACROPHAGES REDUCES TUMOR AND METASTASIS GROWTH ...... 70 3.5.1. REDUCED VESSEL DENSITY IN MACROPHAGE-DEPLETED TUMORS AND METASTASIS ................................................................................................................... 71 3.5.2. DIFFERENT ENDOTHELIAL CELL ACTIVATION IN LM OF MACROPHAGE-DEPLETED MICE. ...................................................................................................................73 4. DISCUSSION...............................................................................................................75 4.1. SEARCHING FOR MOUSE MODELS OF METASTATIC C RC ...................................... 76 4.2. THE THERAPEUTICAL IMPLICATION OF VASCULAR CO-OPTION.................................77 4.3. THE INFLUENCE OF MACROPHAGES ON PATIENT OUTCOME..................................78 4.4. VEGFR1* MACROPHAGES CONTRIBUTE TO METASTATIC ANGIOGENESIS ............. 79 4.5. THE VEGFR1 PROGNOSTIC VALUE..................................................................... 80 4.6. CIRCULATING MONOCYTES, BIOMARKERS FOR CRLM RELAPSE? .......................... 81 4.7. MACROPHAGE ONTOGENY: DIVERSITY EXPLAINED BY THE MICROENVIRONMENT. 82 4.8. NEW OPPORTUNITIES FOR TREATING M CRC.........................................................83 4.9. CONCLUSIONS AND FUTURE DIRECTIONS..............................................................85 5. MATERIALS AND METHODS...........................................................................................87 5.1. MATERIALS............................................................................................................87 5.1.1. CHEMICALS AND REAGENTS ................................................................... 87 5.1.2. CONSUMABLES..................................................................................... 88 5.1.3. EQUIPMENT .......................................................................................... 88 5.1.4. KITS 5.1.5. QRT-PCR REAGENTS, NUCLEOTIDES AND BUFFERS .......................................... 89 5.1.6. QRT-PCR PRIMERS.....................................................................................89 5.1.7. CELLS...........................................................................................................89 5.1.8. CELL CULTURE REAGENTS.................................................................................90 5.1.9. RECOMBINANT PROTEINS AND COMPOUNDS .................................................. 90 5.1.10. FLOW CYTOMETRY ANTIBODIES....................................................................... 91 5.1.11. MAGNETIC ASSOCIATED CELL SORTING ANTIBODIES ............................................ 92 5.1.12. PRIMARY ANTIBODIES....................................................................................92 5.1.13. SECONDARY ANTIBODIES AND FLUORESCENT PEPTIDES.....................................93 5.1.14. ADDITIONAL STAINING REAGENTS..................................................................... 93 5.1.15. WESTERN BLOT REAGENTS .............................................................................. 94 5.1.16. SOLUTIONS AND BUFFERS ............................................................................... 94 5.2. METHODS.......................................................................................................... 96 5.2.1. ANIMALS .................................. 96 5.2.2. IN VIVO METHODS.........................................................................................96 5.2.2.1. METASTATIC MOUSE MODEL OF C R C ......................................................................... 96 5.2.2 2. MAGNETIC CELL SEPARATION.....................................................................................96 5.2.2.3. FLOW CYTOMETRY AND FLUORESCENT ACTIVATED CELL SORTING (FACS) ....................... 97 5 2.2.4. ISOLATION OF MURINE MACROPHAGES......................................................................... 98 5.2.3. IMMUNOHISTOCHEMISTRY (IRC)...................................................................99 5.2.3.1. PARAFFIN AND CRYO EMBEDDING OF MOUSE TISSUE ................................................... 99 5.2.3.2. DEPARAFFINIZATION AND DEHYDRATION OF PARAFFIN SECTIONS.......................................99 5.2.3.3. IHC STAINING............................................................................................................. 99 5.2.4. IMMUNOFLUORESCENCE STAINING..................................................................99 5.2.5. CELL CULTURE METHODS .............................................................................. 100 5.2.5.1. CELL CULTURE............................................................................................................ 100 5.2.5.2. MACROPHAGE DIFFERENTIATION..................................................................................100 5.2.5.3. CONDITIONED MEDIUN (C M )...................................................................................101 5.2.6. ANGIOGENIC ASSAYS................................................................................. 101 5.2.6.1. SPROUTING ASSAY..................................................................................................101 5.2.6 2. TUBE FORMATION ASSAY.......................................................................................... 101 5.2.6.3. TRANSWELL MIGRATION ASSAY................................................................................. 102 5.2.7. BIOCHEMICAL METHODS ............................................................................. 102 5.2.7.1. PROTEIN ISOLATION.................................................................................................... 102 5.2.7.2. SDS-PAGE AND WESTERN BLOT............................................................................ 102 5.2.8. MOLECULAR BIOLOGY....................................................................................103 5.2.8.1. RNA ISOLATION.......................................................................................................103 5.2.8.2. QUANTITATIVE REAL-TIME PCR (QP C R ) ................................................................. 103 5.2.9. RNA-SEQ..................................................................................................103 5.2.9.1. DATA ACQUISITION................................................................................................... 103 5.2.9.2. DATA ANALYSIS........................................................................................................104 5.2.10. STATISTICAL ANALYSIS...................................................................................104 6. REFERENCES.............................................................................................................107 7. APPENDIX................................................................................................................ 119 7.1. SUPPLEMENTARY FIGURES.................................................................................119 7.2. SUPPLEMENTARY TABLES..................................................................................127 8. PUBLICATIONS...........................................................................................................133 9. ACKNOWLEDGEMENTS.............................................................................................. 135 10. EIDESSTATTLICHE ERKLAERUNG.................................................................................137
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spellingShingle	Freire Valls, Aida The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
subject_GND	(DE-588)4113937-9
title	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
title_auth	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
title_exact_search	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
title_full	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer presented by M.Sc. Aida Freire Valls
title_fullStr	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer presented by M.Sc. Aida Freire Valls
title_full_unstemmed	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer presented by M.Sc. Aida Freire Valls
title_short	The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
title_sort	the interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer
topic_facet	Hochschulschrift
url	http://d-nb.info/1171582099/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030870493&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT freirevallsaida theinterplaybetweenmacrophagesandangiogenesisinlivermetastasisofcolorectalcancer

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