Dokument

Summary:
Ovarian carcinoma kills hundreds of thousands of women annually. High grade serous carcinoma is the most common subtype. Like other tumors, high grade serous ovarian carcinoma successfully evades elemination by the immune system - for example, a pro-inflammatory activation state of macrophages is suppresed. Unlike other cancer types, it spreads not only via blood and the lymphatic system, but via peritoneal fluid and growth along the omentum. It is often acompanied by a malignant accumulation of peritoneal fluid, called ascites in which tumor cells and host (immune) cells, such as macrophages, float and interact. Prior to the publications summarized in this cumulative dissertation, no detailed map of these interactions had been published. We compiled a detailed picture of mediators and receptors based on gene expression data from macrophages and tumor cells harvested from the ascites of patients undergoing primary surgery. Though the map is of limited accuracy due to the additional layers of regulation between gene expression and actual effector molecule release, it revealed candidates which were tested for their association with relapse free survival. Among the strongly (negatively) associated mediators were arachidonic acid and its derivatives as well as cytokines such as IL-6 and IL-10. To discern the tumor influence on macrophages, tumor associated macrophages and monocyte derived (i.e. cultured) macrophages were compared. They showed large differences in their gene expression patterns and activation state. The experiment however could not distinguish between tumor and cell culture induced effects. Therefore a more appropriate control, peritoneal macrophages from non-malignant diseases, was sought. These peritoneal macrophages turned out to be very similar to tumor associated macrophages in both gene expression and activation state, suggesting that the tumor ascites environment does not induce, but rather suppresses, a change in activation state. The only discernible difference was a cluster of co-regulated genes related to extra cellular matrix reorganization, which hints that macrophages might play a role in establishing metastases within the coelom. A second focus of this thesis is the role of the nuclear receptor PPAR\betadelta in tumor associated macrophages. We found PPAR\betadelta to be induced during the differentiation of monocytes into macrophages and ascites to contain PPAR\betadelta ligands, e.g. arachidonic acid. PPAR\betadelta signaling was accordingly activated and rendered tumor associated macrophages unresponsive to further stimulation by (synthetic) PPAR\betadelta agonists but susceptible to inverse agonists. Using \invitro{} differentiated macrophages and \exvivo{} tumor associated macrophages we could show that PPAR\betadelta induces a distinct activation state in macrophages and were able to characterize its target gene network in great detail.

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