Since there is accumulating evidence that STAT3 is constitutively activated in PDAC and important for the progression and maintenance of this disease, the goal of this thesis was to establish a PDAC model in the lab to further investigate and characterize if the synergistic effect of VSV with STAT3 inhibition would also be effective on this cancer type. Aiming to unravel as many characteristics as in vitro studies allow, this study utilized not just 2D and 3D systems, but also cocultural approaches on both molecular and morphological levels.
Pancreatic ductal adenocarcinoma (PDAC) is considered as a very severe diagnosis because of the poor survival rates and the aggressive nature. Further investigations show the high complexity of the mutational cascades in PDAC initiation and progression. The importance of the tumor microenvironment is clarified, but as different studies led to paradoxic results in targeting the stroma, it gives us evidence that it is just poorly understood yet. Given the limitations of current treatments and the failure of various novel approaches, a necessity of further investigating new therapeutic options is unquestionable.
Contents
I. Introduction
1.1 Pancreatic cancer
1.1.1 PDAC development and progression
1.1.2 Microenvironment
1.1.3 Current treatment options and their limitations
1.2 Oncolytic viruses
1.2.1 Vesicular stomatitis virus
1.3 Signal transducer and activator of transcription 3
1.4 Aim of this thesis
II. Material
2.1 Cell lines
2.2 Reagents
2.3 Antibodies
2.4 Consumables
2.5 Appliances
III. Methods
3.1 Cell culture
3.1.1 3D cell culture systems
3.1.2 Co-culture systems
3.2 Viability assay
3.3 Tissue culture infection dose
3.4 Western blotting
3.5 Flow cytometric analysis
3.6 Confocal microscopy
3.7 Luciferase assay
3.7.1 Plasmid DNA preparation
3.7.2 Transfection
3.7.3 Interferon induction and response
3.8 Scratch assay
IV. Results
4.1 PDAC cells are susceptible to rVSV-GFP-mediated oncolysis in vitro
4.2 S3I-201 causes reduction of PDAC cell viability in vitro
4.3 Combination therapy enhances PDAC killing and safety
4.4 Combinational therapy in the microenvironment
4.5 Effects of S3I-201 and VSV in co-culture
4.6 Combination therapy in 3D
4.7 Inhibition of migration
V. Discussion
VI. List of Abbreviations
VII. References
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Téléchargez vos propres textes! Gagnez de l'argent et un iPhone X.