Analyse von Zytokinen im Aszites des Ovarialkarzinoms und Assoziationen mit der klinischen Progression

Das Ovarialkarzinom ist das dritthäufigste gynäkologische Malignom in der westlichen Welt, weist jedoch die höchste Mortalität unter ihnen auf. Als „stummes“ Karzinom wird das Ovarialkarzinom zumeist erst in fortgeschrittenen Stadien diagnostiziert. Dann liegt meist bereits eine Metastasierung in di...

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1. Verfasser: Schwörer, Anne-Marie
Beteiligte: Müller-Brüsselbach, Sabine (PD, Dr. rer. physiol.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2016
Molekularbiologie und Tumorforschung
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Inhaltsangabe: Ovarian cancer is the third most common gynecological cancer in western civilization, but shows the highest mortality among them. Because of its vague symptoms, it is mostly diagnosed at advanced stages. At this stage, metastasis throughout the peritoneal cavity has already taken place and malignant ascites is being produced. In order to get understand the role of some cytokines in malignant ascites, the concentration of certain cytokines and the tumor marker CA-125 (in the following referred to as cytokine) was determined in samples of malignant ascites from 31 ovarian cancer patients. Subsequently, correlations among these results and with respect to associations with the relapse-free survival were measured. Significant differences in relapse-free survival of patients between the two groups “low” and “high” cytokine level were identified for the following cytokines: CA-125 (***p=0,005), IL-6 (*p=0,01), IL-10 (****p<0,0001), LIF (*p=0,0162), S100 A8 (*p=0,0225) and TGF- β (*p=0,0378). In these cases, high cytokine levels were significantly associated with shorter relapse-free survival. Results with respect to median relapse-free survival showed significant differences for CA-125 (27 vs 13 months), IL-6 (27 vs 13,5 months), IL-10 (26 vs 12 months), LIF (26 vs 13 months), S100 A8 (23 vs 12,5 months) und TGF- β (27 vs 15 months). According to above findings, higher cytokine levels were associated with reduced median relapse-free survival. Additionally, cytokine levels proved to be highly predictive among themselves. We found a strong correlation between IL-6 and LIF (r=0,802; ***p<0,001), both of which are STAT3-activating cytokines. Furthermore there was a strong correlation between M-CSF and CA-125 (r=0,783; ***p<0,001), which are both secreted by tumor cells and might be considered as markers for tumor burden. As target genes of TGF- β, both S100A8 and ANGPTL4 showed a strong correlation with TGF- β level: (r=0,628; ***p<0,001) and (r=0,593; ***p<0,001) respectively. A moderate correlation could be shown for STAT3-activating cytokines IL-6 and IL-10 (r=0,385; *p<0,05). Correlation of cytokine concentrations and BMI revealed significance only for Leptin (r=0,655; **p<0,005). The in-vitro experiments with ovarian cancer cell lines indicated a pro-proliferative effect of Leptin. Analysis of the Leptin induced signaling pathways could not confirm literature findings pointing to STAT3 involvement, yet induction of MAPK/ERK-signaling and PI3K/AKT was detectable.