The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer:
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
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Heidelberg
[2018]
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| Beschreibung: | 137 Seiten Illustrationen, Diagramme 30 cm |
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| 245 | 1 | 0 | |a The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer |c presented by M.Sc. Aida Freire Valls |
| 264 | 1 | |a Heidelberg |c [2018] | |
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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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| author | Freire Valls, Aida |
| author_GND | (DE-588)114490904X |
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| spelling | Freire Valls, Aida Verfasser (DE-588)114490904X aut The interplay between macrophages and angiogenesis in liver metastasis of colorectal cancer presented by M.Sc. Aida Freire Valls Heidelberg [2018] 137 Seiten Illustrationen, Diagramme 30 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Ruperto-Carola-University of Heidelberg 2018 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1171582099/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf 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 Inhaltsverzeichnis |
| 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 |
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