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Complete Dissertation VU Research Portal Signaling at the tumorigenesis-inflammation interface: developing systems immunology to resolve a paradox Abulikemu, A. 2017 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Abulikemu, A. (2017). Signaling at the tumorigenesis-inflammation interface: developing systems immunology to resolve a paradox. 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Oct. 2021 Signaling at the Tumorigenesis-Inflammation Interface: developing Systems Immunology to resolve a Paradox Ablikim Abdukerim PhD thesis with summary in Dutch Department of Molecular Cell Biology Faculty of Earth and Life Sciences VU University Amsterdam, The Netherlands Printed by Amsterdam University Press, Amsterdam VRIJE UNIVERSITEIT Signaling at the Tumorigenesis-Inflammation Interface: developing Systems Immunology to resolve a Paradox ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Aard-en Levenswetenschappen op dinsdag 28 maart 2017 om 11.45 uur in de aula van de universiteit, De Boelelaan 1105 Door Abulikemu Abudukelimu geboren te Urumqi, Xinjiang, China promotoren: prof.dr. H.V. Westerhoff prof.dr. S.M. van Ham copromotor: dr. M. Barberis Members of the Doctoral Examination Committee: prof. dr. F.J. Bruggeman VU University Amsterdam, the Netherlands dr. K. Krab VU University Amsterdam, the Netherlands prof. dr. R.E. Mebius VU University Medical Center , the Netherlands dr. F. A. M. Redegeld Utrecht University, the Netherlands prof. dr. J.L. Snoep University of Stellenbosch and VU University Amsterdam, South Africa and the Netherlands prof. dr. A.H.C. van Kampen University of Amsterdam, the Netherlands dr. G.J. Wolbink Amsterdam Rheumatology Center and Sanquin, the Netherlands To my beloved parents and sister And my niece Table of Contents Chapter 1: General Introduction 1.1 Inflammation and immunity are driven by various interactions in the immune system 1.1.1 Cell-mediated immunity for bacterial infection .................................................. 2 1.1.2 Cell-mediated immunity for viral infection .......................................................... 4 1.2 The immune system and cancer 1.2.1 Cellular-immunity for cancer ............................................................................ 6 1.2.2 Immunotherapy strategies to combat cancer. ..................................................... 9 1.3 Cancer-related inflammatory biomarkers: TNF-α, tryptase and Ig-free light chains (FLCs) .............................................................................................................. 10 1.4 Mast cells 1.4.1 Mast cell activation ........................................................................................ 12 1.4.2 Pro-cancer functions of mast cells . .................................................................. 15 1.4.3 Anti-cancer functions of mast cells. .................................................................. 16 1.5 Mast cells, inflammation and cancer: systems biology might matter ................ 19 1.6 Aims and overview of the thesis ........................................................................ 20 Chapter 2: FLC-Mediated Mast Cell (in) Activation and Its Predictable Effects on Acute and Chronic Inflammation 2.1 Introduction ......................................................................................................... 22 2.2 Methods and parameters ................................................................................... 24 2.3 Results ................................................................................................................ 27 2.4 Discussion .......................................................................................................... 36 Chapter 3: Inflammation-oriented Anti-Tumor Targets in a Complex Model for Mast-cell Mediated Tumorigenesis 3.1 Introduction ......................................................................................................... 44 3.2 Material and Methods 3.2.1 Immunohistochemistry analysis ....................................................................... 47 3.2.2 In silico model and its analyses. ........................................................................ 48 3.3 Results 3.3.1 Human and murine tumor biopsies harbor disperse activated mast cell .... 51 3.3.2 Modeling the tumor-associated inflammatory network. ..................................... 55 3.4 Discussion ........................................................................................................... 64 3.5 Supplementary materials: in vivo validation of the in silico model 3.5.1 Anti-FLC peptides redress tumor growth in vivo. ................................................ 66 3.5.2 Supplemental experimental methods. ............................................................. 67 Chapter 4: Dynamics of a Model of Innate Immunity: Complex (bi-) Stability, Flares, Irreversible Transitions, and Sensitivities 4.1 Introduction ......................................................................................................... 78 4.2 Methods .............................................................................................................. 80 4.3 Results 4.3.1 Instability, flares of infection and a therapy thereof ........................................... 81 4.3.2 Bimodal sensitivity analysis of innate inflammation............................................. 82 4.3.3 Bi-stability, irreversible transition and fata switching in innate inflammation ....... 84 4.3.4 Jumping the bi-stability barrier: fibroblast therapy of innate inflammation. ..................... 91 4.4 Discussion 4.4.1 Diverse stabilities of a model of innate immunity ............................................. 99 4.4.2 Robustness of innate immunity . .................................................................... 101 4.4.3 An important role for bystander cells? ........................................................... 102 4.5 Supplementary material .................................................................................. 103 Chapter 5: Mast Cells as Potential Therapeutic Targets for Anti-Tumor Therapy 5.1 Introduction 5.1.1 Mast Cell Biology 5.1.1.1 Origin of mast cells ................................................................................. 113 5.1.1.2 Phenotype ............................................................................................ 113 5.1.1.3 The mast cell and innate immunity ......................................................... 114 5.1.1.4 The mast cell and adaptive immunity ...................................................... 114 5.2 Mast cells and cancer diagnosis ....................................................................... 115 5.3 Mast cells as drug target 5.3.1 Targeting mast cell degranulation .............................................................. 118 5.3.2 Targeting mast cell tryptase . ..................................................................... 119 5.3.3 Anti-IgE therapy in cancer . ....................................................................... 120 5.4 Stem Cell Factor (SCF) and the c-kit Mediated Signaling Pathway 5.4.1 Stem Cell Factor ........................................................................................ 120 5.4.2 C-kit. ............................................................................................................ 121 5.4.3 Inhibition of SCF-C-kit signaling. .......................................................................... 122 5.5 Concluding remarks .......................................................................................... 125 Chapter 6: Inflammation and Cancer: how could Systems Biology help unravel the Link? 6.1 The inflammation system perspective ............................................................. 128 6.2 The cancer system perspective ........................................................................ 130 6.3 Personalized medicine ...................................................................................... 132 6.4 Future directions .............................................................................................. 134 Chapter 7: Further Understanding and Initial Validation Thereof (Supplemental material) S7.1 Methods .......................................................................................................... 136 S7.2 Results ............................................................................................................
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