Browsing by Subject "Tumorzelle"

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Der Einfluss des Osteoblasten- und Tumorzellfibronektins auf die Immunzellen
(2014) Kraft, Sabrina; Nakchbandi, Inaam
The function of the osteoblastic niche for the hematopoesis is an aim of recent research. This work shows, that fibronectin originating from osteoblasts leads to an increase of hematopoetic stem cells and granulocyte monocyte progenitors (GMP). The most abundant fibronectin isoform in OB is EDA. This thesis gives first evidence that there is a relationship between the differentiation of HSPC, GMPs and EDA. These results were associated with a changed expression in two intergrins, α4ß7 and α5ß1. The impaired differentiation of GMPs also leads to a decrease of myeloid and granulocyte progenitor cells. Additionally, myeloid progenitors displayed an increased production of cytokines inhibiting tumor growth. There also was a decrease of myeloid derived suppressor cells (MDSC), which are normally contributers of tumor growth through a t-cell suppression dependent mechanism and the production of tumor proliferating cytokines. The decrease of these cells should be benefical for the inhibition of tumor growth and indeed there was a decrease of tumor growth in two tumor models (murine melanoma and human breast cancer bone metastases). These results are due to the decreased number of MDSCs and the increased production of tumor proliferating cytokines. This effect was t-cell independent. A correlation between OB-FN and the inhibited tumor growth were verified by adoptive transfer experiments with in vitro differentiation of myeloid progenitor cells in presence and absence of EDA and the induction of melanoma. The presence of EDA during the differentiation was able to induce an increase of tumor growth again. This thesis presents for the first time the influence of osteoblast fibronectin in immune cell differentiation and indirectly on tumor growth. The second part of this work suggests, that the deletion of fibronectin in tumor cells, especially of EDA, leads to an inhibted growth of human breast cancer cells in bone and in an increased number of macrophages in the tumor. The analysis of the cytokine production of tumor-associated macrophages showed a tumor inhibiting cytokine profil, which suggest, that the macrophages in the tumor are so called M1-macrophages. M1-macrophages are known to inhibit tumor growth. The depletion of macrophages with clodronate lipsomes in mice, leads indeed to an increase of tumor growth in absence of the tumor cell fibronectin. For the first time it was therefore show an influence of a changed extracellular matrix production on macrophages in tumors.
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.