We observed striking correlation of P cadherin and E cadherin mRNA levels supporting a possible associ Discussion The EMT status reflects features of cancer cells that favor cell migration and invasion, characteristics that are linked to metastasis. Epithelial like cells are crucially character ized by E cadherin and mesenchymal like cells by N cadherin expression. In cancer, the EMT status reflects the issue of complex cell signaling mechanisms including RTK pathways. Aberrant signaling of RTKs has been de scribed in bladder cancer. Therefore, TKIs are studied for therapy of bladder cancer however, the therapeutic re sponses vary and are difficult to predict. Here, we investigated the EMT status in bladder cancer cell lines and tested whether the EMT status is associated with therapeutic responses towards TKI 258.
Most importantly, ation of P cadherin with epithelial characteristics. This finding is in line with studies where P cadherin was ob served to be enhanced in low grade non muscle invasive bladder cancer indicating epithelial differentiation. Other studies revealed correlation of P cadherin levels with increasing tumor and grading stage indicating a mes enchymal characteristic. In contrast, the role of N cadherin and E cadherin in EMT is clearly defined. Therefore, calculation of an EMT score based on these cadherin subtypes appeared reasonably and revealed corre lations with TKI258 responses in all cell assays performed. Noteworthy, RTK signaling is related to the expres sion of epithelial and mesenchymal markers.
In particu lar, FGFR3 mRNA correlated with E cadherin mRNA as confirmed in the cell lines in our study. Further more, FGFR1 mRNA expression correlated with the mesenchymal marker N cadherin. Thus, the analysis of the EMT may be an alternate clue to predict responses towards inhibition of RTK signaling in cancer cells without the need to identify possible aberrations of RTK or downstream components by molecular diagnostics. Noteworthy, pre diction of cellular responses towards TKI 258 solely based on mutation studies of FGFR have failed and the identification of superior biomarkers is desirable. The analysis of EMT parameters as performed in our study in human cancer cell lines would be also applic able for tumor tissue samples. Restrictively, it has to be addressed that TKI 258 targets several RTKs namely those of the ligands VEGF, PDGF and FGF that represent growth and angiogenic factors.
Thus, in vivo effects of TKI 258 are certainly more complex and comprise effects on tumor angiogenesis. Moreover, ef fects of TKI 258 have not only been Batimastat attributed to inhibition of RTKs. Namely, topoisomerase II has been demonstrated as target of TKI 258 causing cytotoxic DNA double strand breaks. Conclusions Aberrant cellular processes that contribute to bladder tumorigenesis comprise altered signaling of RTKs.