Die Bedeutung des Wnt/β-Catenin-Signalwegs für die Radiotherapieresistenz des Rektumkarzinoms sowie von Normalgewebe am Beispiel von RPE-1-Zellen

The impact of the Wnt/β-catenin pathway on the radiotherapy resistance in rectal cancer and normal tissue using the example of RPE-1 cells

by Janneke Möller
Doctoral thesis
Date of Examination:2020-11-03
Date of issue:2020-09-22
Advisor:PD Dr. Marian Grade
Referee:PD Dr. Marian Grade
Referee:Prof. Dr. Dieter Kube
Persistent Address: http://dx.doi.org/10.53846/goediss-8190

 

 

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Abstract

English

Colorectal cancer is one of the most common cancers worldwide. The standard treatment for locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by surgery. However, the response to chemoradiotherapy is highly heterogeneous and ranges from complete response to complete resistance. Thus, patients with a priori resistant tumors receive a costly treatment and are exposed to its potential side-effects without benefit. Hence, it seems sensible to individualize the treatment. Therefore, a better understanding of the underlying mechanisms of the treatment resistance is strongly needed. Gene expression analyses showed an upregulation of the transcription factor TCF7L2 in primary rectal cancers that are resistant to chemoradiotherapy. TCF7L2 plays a central role in the Wnt/β- catenin pathway. Kendziorra et al. suggested that silencing of TCF7L2 in the resistant colorectal cancer cell lines SW480 and SW837 results in sensitization to radiotherapy. The aim of this thesis is to investigate the influence of the Wnt/β-catenin pathway on the (chemo-) radiotherapy resistance in the normal cell line RPE-1. Therefore, the Wnt/β-catenin pathway was stimulated both externally using the ligand Wnt3a as well as internally via overexpression of mutated β-catenin (S33Y). Subsequently, the sensitivity of the cells to (chemo-) radiotherapy was determined. It was shown that both types of stimulation produce significant increase of (chemo-) radiotherapy resistance in RPE-1 cells. Thus, our results show that the activity of the Wnt/β-catenin pathway affects the (chemo-) radiotherapy resistance in malignant and non-malignant cells. Consequently, the specific manipulation of the Wnt/β-catenin pathway appears to be a promising approach in cancer treatment.
Keywords: treatment resistance; colorectal cancer; radiotherapy; Wnt/β-catenin signaling; RPE-1 cells
 
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