Charakterisierung von Tumorstammzellen in pankreatobiliären Karzinomen: Der Notch-Signalweg als potentielles Therapieziel [thesis]

Elisabeth Seidel, Universitätsbibliothek Der FU Berlin
2020
Pancreatic cancer and cholangiocellular carcinoma are aggressive tumors with high mortality rates and poor treatment options. Recent reports describe the Notch pathway as highly relevant for a variety of fundamental cellular processes in the embryonic and adult organism. Therefore its deregulation can induce tumorigenesis. Moreover, cancer stem cells (CSC) are discussed as a source for the formation, chemotherapeutical resistance and recurrence of tumors. Through Fluorescence-activated Cell
more » ... -activated Cell Sorting (FACS)-Analysis, the existence of cancer stem cells in eCCA- and PDAC cell lines as well as the presence of five Notch-associated proteins in this population was examined. Additionally, the effect of a specific Notch-inhibitor (DAPT-IX/GSI) and the chemotherapeutic gemcitabine on CSCs in eCCA- and PDAC cell lines was explored. To investigate whether these pharmalogical agents also affect the entire cell population, TUNEL-staining indicated the rate of apoptosis in eCCA- und PDAC cell lines. Additionally, CellToxGreen Cytotxity Assay was used to demonstrate the cytotoxity potential of gemcitabine and GSI in PDAC- and eCCA cell lines. In the here presented study, FACS-analysis showed that the CSC population in eCCA cell lines is significantly larger than in PDAC cell lines (p<0.0001). Contrary to the effect on PDAC cell lines, GSI-IX/DAPT (p<0.008) and Gemcitabin (p<0.04) treatment caused a significant decrease of the eCCA-CSC populations. The CellToxGreen Cytotoxity Assay indicated that GSI-IX/DAPT and Gemcitabin treatment decreases cell viability of both ECC cell lines significantly (p<0.05), but reveals only moderate effects on PDAC cell lines. The rate of apoptosis underlines these results. In conclusion, the eCCA und PDAC cell lines are different due to the percentage of CSCs and the expression of Notch-associated proteins. Particularly in regard to its effect on the CSC population, Notch-Signaling may be of therapeutic value in eCC, but seems to show no effect on more aggressive PDAC. We could hereby fu [...]
doi:10.17169/refubium-27523 fatcat:dvzp7sp5szgaxphh2foicfrmlq