Die Rolle der IGF-Achse in Kombination mit anderen Wachstumsfaktor-Signalwegen bei der Resistenz oder dem Ansprechen von kolorektalen Karzinomen auf eine Radiochemotherapie

In the Western world cancer represents one of the major health problems. Colorectal cancer (CRC) is the third most common tumor incidence. In advanced disease, in most cases a combined radiochemotherapy (RCT) is performed, where cytostatics such as 5-fluorouracil or oxaliplatin are administered in addition to irradiation. Because the cytotoxic drugs used act not only against tumor cells, the use of these drugs often cause severe side effects such as stomach and intestinal problems, myelosuppression and alopecia. Therefore, new therapeutic approaches try to find new treatment goals that are more cancer cell-specific, such as the inhibition of different receptor tyrosine kinases. In the tumor and surrounding tissues many receptor tyrosine kinases and their ligands are often deregulated and play an important role in the regulation of tumor growth, tumor angiogenesis and metastasis. In this work it was demonstrated in vitro for the three colorectal carcinoma cell lines DLD-1, SW837 and Caco2 that the concomitant inhibition of the Insulin-like Growth Factor-I Receptor (IGF-IR) and the Epidermal Growth Factor Receptor (EGFR) with the tyrosine kinase inhibitors AEW-541 (IGF-IR inhibitor) and erlotinib (EGFR inhibitor) leads to a significantly enhanced therapeutic effect of the 5-fluorouracil based RCT. This effect could also be confirmed in vivo by using xenograft tumors of the cell line SW837. In the CRC cell lines SW480 and DLD-1 we were able to detecthybrid receptors between the IGF-IR and the EGFR by using both co-immunoprecipitation and proximity ligation assays. In addition, it was shown that a stimulation of the receptors by their ligands leads to increased EGFR/IGF-IR hybrid receptor formations. Further analysis showed that both receptor ligands are necessary for the induced heterodimerization and both receptors have to be functional. By using the proximity ligation assay EGFR/IGF-IR hybrid receptors were also detected in situ in human rectal tumor specimens. In the last part of the present work, the significance of the Platelet-derived Growth Factor Receptor β (PDGFR-β) was studied in CRC cells. In SW480 and DLD-1 cells, inhibition of PDGFR-β using specific siRNAs moderately reduced the proliferation rate via a decreased activity of the PI3K signaling pathway. The treatment of these CRC cell lines with the PDGFR-β inhibitor Ki11502 led to a strong decrease in the proliferation rate and to changes in the cell cycle which was caused by a decreased expression of Cyclin-B1. Further analyses showed that the inhibitor Ki11502, in addition to the blockade of the PDGFR-β, inhibited the ckit receptor (v -kit Hardy - Zuckerman 4 feline sarcoma viral oncogene homolog) and the cell membrane associated cytoplasmic tyrosine kinase SRC (V -src sarcoma (Schmidt -Ruppin A-2) viral oncogene homolog) in CRC cells.