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dc.contributor.advisor Burfeind, Peter Prof. Dr.
dc.contributor.author Oberthür, Rabea
dc.date.accessioned 2016-12-06T10:26:43Z
dc.date.available 2016-12-06T10:26:43Z
dc.date.issued 2016-12-06
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002B-7CC8-1
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610
dc.title Analysis of the function of the IGF1R during the development and therapy of colorectal cancer de
dc.type doctoralThesis de
dc.contributor.referee Dobbelstein, Matthias Prof. Dr.
dc.date.examination 2016-07-18
dc.description.abstracteng The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that is overexpressed in a variety of human malignancies, including colorectal cancer (CRC). In the present study, the role of the IGF1R during intestinal development, colonic tumor formation and progression, and during the therapy of CRC was analysed. For this reason, two transgenic mouse models were generated. The Villin-TRE-IGF1R mouse line drives villin-guided expression of the human IGF1R gene specifically in epithelial cells of the intestine. The Villin-CreERT-Igf1r mouse line is an inducible intestine-specific mouse model for the knockout of endogenous Igf1r driven by the villin promoter. To investigate if IGF1R overexpression is capable of inducing intestinal tumor development, IGF1R overexpression was induced in Villin-TRE-IGF1R mice, but villin-guided IGF1R overexpression was not sufficient to induce intestinal tumor formation. Quantification of the different epithelial cells of the intestine indicated that the IGF1R promotes epithelial cell proliferation and inhibits epithelial cell differentiation, pointing to a role of the IGF1R in normal intestine homeostasis. In order to study the role of the IGF1R during colonic tumor progression and invasion, tumor formation was induced in Villin-TRE-IGF1R mice by the carcinogen azoxymethane (AOM) or the combination of AOM and the inflammatory agent dextran sulfate sodium (DSS), respectively. IGF1R overexpression was shown to promote intestinal tumor progression and invasion, i.e., IGF1R overexpressing mice displayed a higher number of tumors with increasing stage and the development of even invasive tumors. In the Villin-CreERT-Igf1r mouse model, the differentiation and proliferation processes of the intestinal epithelial cell types were also characterised, pointing again towards a role of the IGF1R during these processes. The Villin-CreERT-Igf1r mice were also treated with AOM or AOM/DSS, respectively. Igf1r knockout mice revealed a reduced number of colonic tumors with advanced stage compared to control mice, indicating again that the IGF1R promotes colonic tumor progression. Since it is known that the IGF1R is highly upregulated in CRC, the IGF1R was predicted to be an important molecular target to treat patients with advanced CRC. Xenograft experiments were performed to study the effect of simultaneous inhibition of the IGF1R and the epidermal growth factor receptor (EGFR) using the small molecule kinase inhibitors AEW541 and erlotinib, respectively, in combination to 5-fluoruracil-based radiochemotherapy (RCT). In SW837 xenograft mice tumor progression, tumor volume and weight were significantly reduced after simultaneous treatment with AEW541/erlotinib, indicating that simultaneous inhibition of the IGF1R and EGFR has greater effects on tumor cell survival than single inhibition of either the IGF1R or EGFR in combination with RCT. In conclusion, the results of the present study display a pivotal role of the IGF1R in CRC. The data indicate that IGF1R overexpression reduces epithelial cell differentiation and promotes proliferation. In fact, the results demonstrate that IGF1R overexpression per se is not sufficient to induce colonic tumor formation, but indicate that IGF1R overexpression promotes intestinal tumor progression. These findings can be used to investigate new therapeutic strategies, in which tumor progression is prevented by the inhibition of the IGF1R. de
dc.contributor.coReferee Dressel, Ralf Prof. Dr.
dc.subject.eng Colorectal cancer de
dc.subject.eng IGF1R overexpression de
dc.subject.eng Igf1r knockout de
dc.subject.eng Radiochemotherapy de
dc.subject.eng EGFR de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7CC8-1-5
dc.affiliation.institute Medizinische Fakultät
dc.subject.gokfull Medizin (PPN619874732) de
dc.identifier.ppn 873949676

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