Der Einfluss von NOTCH-Rezeptoren auf die Radiochemotherapie-Sensitivität kolorektaler Tumorzellen

The impact of NOTCH receptors on the radiochemotherapy sensitivity of colorectal cancer cells

by Alena Marie Siebert
Doctoral thesis
Date of Examination:2025-01-23
Date of issue:2025-01-13
Advisor:PD Dr. Marian Grade
Referee:PD Dr. Marian Grade
Referee:Prof. Dr. Jürgen Wienands
Persistent Address: http://dx.doi.org/10.53846/goediss-11010

 

 

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Abstract

English

The treatment of colorectal cancer remains a challenge to this day. Despite numerous advances in therapy, the prognosis, especially in advanced or metastatic stages, remains poor. A current standard therapy for locally advanced rectal carcinomas is combined radiochemotherapy followed by surgical resection. The response to this neoadjuvant therapy is highly heterogeneous, ranging from complete remission to complete resistance. One promising approach is to resensitize tumor cells to radiochemotherapy by manipulating cell signaling pathways. In previous work, our research group was able to identify the NOTCH signaling pathway as a potential target. RNAi-based silencing of the NOTCH transcription factor RBPJ led to increased rectal cancer cell lethality under radio(chemo)therapy. In this thesis, the role of NOTCH receptors 1, 2, and 3 in the response to radio(chemo)therapy was evaluated. To this end, the respective receptors were silenced using siRNA in colorectal cancer cells. Subsequently, the sensitivity of the cells to radio(chemo)therapy was determined. The results showed that in cells with high NOTCH receptor expression, receptor inhibition led to significant resensitization to radio(chemo)therapy in all but one case. In the exception, increased resistance to radiotherapy was observed. These findings highlight the importance of NOTCH receptors in mediating radio(chemo)resistance in colorectal cancer, as well as the need for a differentiated approach regarding the role of the individual receptors.
Keywords: Colorectal cancer; NOTCH Receptors; Chemoradiotherapy resistance; NOTCH Signaling