Die Rolle des SCF/c-Kit-Signalweges für das klonogene Überleben und Invasionsverhalten nach Photonenbestrahlung in humanen nicht-kleinzelligen Lungenkarzinomzellen

Die Metastasierung eines Tumors ist neben der lokalen Tumorkontrolle entscheidend für das Überleben eines Tumorpatienten. Der SCF/c-Kit-Signalweg ist häufig in Tumoren überexprimiert und beeinflusst Tumorentstehung, die Proliferation, die Migration sowie die Therapieresistenz. In dieser Arbeit sollt...

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Bibliographic Details
Main Author: Saulich, Miriam Farisai
Contributors: Engenhart-Cabillic, Rita (Prof. Dr. med) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2019
Online Access:PDF Full Text
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Survival of cancer patients depents on local tumor controll and metastasis. The SCF/c-Kit pathway is often overexpressed in human tumors leading to an enhanced tumorigenesis, proliferation, migration and therapy resistance. In this work I analysed for the NSCLC cancer cell lines H23 and H226 growing under 2D and 3D culturing conditions whether the pathway influences radiosensitization and may be identified as a respective biomarker. It was also tested whether cancer cell motility determinding metastasis is affected by X-irradiation. Therefor radiosensitization was measured using a colony formation assay. Cell motility was tested with BioCoat™ Matrigel™ Assays. The tested adenocarcinoma (H23) and squamos-cell-carcinoma (H226) cell lines showed a profound variation in the expression of both c-Kit and SCF not being influenced by X-irradiation nor culturing conditions. Comparing 2D with 3D conditions, it was shown that cells grown in 3D were more resistant to X-irradiation as previously reported by others. Knock-down of SCF was generally found to result in no radiosensitization neither under 2D nor 3D conditions. For both cell lines an increase in cell motility was demonstrated when grown in 3D. This can be the result from an EMT-like change as indicated by the enhanced expression of vimentin and N-cadherin and reduction of E-cadherin. This effect was considered to result from a more mesenchymal phenotype under 3D cultural conditions leading to an increase of cell motility. This transition is independent from SCF/c-Kit pathway influencing cell motility. In contrast, X-irradiation did not modulate cell motility or EMT-associated genes. My data show that generally the knockdown of SCF/c-Kit pathway does not result in a radiosensitization. Therefore SCF does not appear to be an effectiv biomarker for radiosensitization in NSCLC. More NSCLC should be characterized to proof my assumptions to be true. In the tested cell lines X-irradiation did not modulate cell motility, which could be harmed by inhibition of SCF/c-Kit pathway. Therefore this inhibition combined with radiotherapy may provide a potential tool in metastatic NSCLC. Summarising my findings indicate that SCF/c-Kit pathway is very important for metastasis of NSCLC, but not for radioresistence.