Browsing by Subject "Signalling mechanisms"

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Glucocorticoid-induziertes Wachstum von Tumorzellen : systematische Quantifizierung, Signalmechanismen und Inhibition
(2010) Gündisch, Sibylle; Jeremias, Irmela
Glucocorticoids (GCs) like Dexamethasone (Dex) are widely used in cancer patients, as cytotoxic drugs in hematopoetic tumors or adjuvants in solid tumors to reduce severe side effects. Nevertheless, GCs are accused to reduce anti-cancer treatment efficiency. Due to preliminary works in our research group the suspicion arose that GCs are able to induce proliferation of tumor cells. The present work provides the first systematic quantification of the proproliferative effects of GCs on tumor cells. Enhanced tumor cell growth was validated by repetitive microscopy, impedance analysis, investigation of DNA synthesis rate, enzymatic activity as well as absolute cell number. It could be proven that 6 out of 10 cell lines from solid tumors showed enhanced proliferation after stimulation with Dex, whereas this phenotype was not limited to one tumour entity or a common origin. In vivo, Dex significantly promoted tumor cell growth in a preclinical mouse model with a lung carcinoma cell line. Furthermore the effect of GCs was detected on 139 primary, patient-derived acute childhood leukemia cells. In 15% GCs were able to increase the in vitro survival of the tumor cells and one sample showed even GC-induced proliferation. Accordingly the anti-apoptotic and pro-proliferative effects of GCs could be proven not only on established solid tumor cell lines but also on primary hematopoetic tumor cells. Knockdown studies in cells of solid tumors showed that GC-induced proliferation was mediated by the glucocorticoid receptor and was further transmitted by the proteinkinases Akt and p38-MAPK. GC-induced proliferation could be prevented by induction of apoptosis which was caused either by clinically applicable substances, as for example Vincristine, or by inducible expression of the pro-apoptotic molecule Caspase-3. To sum up, the present work identified GC-induced proliferation of tumor cells as a new, tumor cell directed side effect of GCs. Of direct translational relevance, our data argue towards a restricted use of GCs during anti-cancer therapy as well as the need for preclinical and clinical studies which demonstrate a more effective and safer application of GCs during anti-cancer therapy.