Funktionelle Analyse von CUX1 in tumorassoziierten Makrophagen des Pankreaskarzinoms

Das Adenokarzinom des Pankreas (PDAC) zeigt eine charakteristische Stromareaktion mit einer hohen Anzahl tumorinfiltrierender Makrophagen (TAM). Obwohl bekannt ist, dass eine hohe Anzahl von TAMs mit einer Verschlechterung der Prognose einhergeht, ist die Rolle dieses Zelltyps im Pankreaskarzinom nu...

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Bibliographic Details
Main Author: Kühnemuth, Benjamin
Contributors: Michl, Patrick (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stromal reaction that is accompanied by high rates of infiltrating macrophages (tumor-associated macrophage - TAM). Even though it is known that a high number of TAMs is associated with a poor prognosis, the role of these cells in PDAC is only partially understood. Several studies have shown that many of the macrophages isolated from human and murine tumors, including PDAC, show a so-called M2 or alternatively activated phenotype which is known to promote tumor progression. Previously, the transcription factor CUX1 was identified as important mediator of tumor progression that is associated with poor prognosis. The tumor-promoting effect of CUX1 was mainly attributed to its pro-migratory, pro-proliferative and anti-apoptotic effects in cancer cells. In this study, CUX1 was identified not only to be expressed in cancer cells but also in TAMs. To further investigate the role of CUX1 in TAMs, CUX1 expression was immunohistochemically analyzed in human pancreatic cancer tissues and a genetic mouse model revealing an increased CUX1 expression in macrophages isolated from cancer tissues. TGF-β, a factor known to be highly expressed in PDAC tissues, was identified as a stimulator of CUX1 expression in macrophages. Using overexpression and knockdown strategies, a panel of cytokines, associated with the M1 phenotype of macrophages, was identified as being repressed by CUX1 in monocytic cells. The molecular mechanisms underlying this repression were further analyzed for the cytokines CXCL10 and CCL5 by reporter assays, DNA-pulldown experiments and chromatin-immunoprecipitations. CUX1 was identified to interfere with the NF-κB signaling pathway by direct interaction with NF-κB p65 leading to reduced binding of NF-κB p65 to the cytokine promoters. In addition, CUX1 reduces acetylation of NF-κB p65 at K310 probably by recruitment of HDAC1. Functionally, CUX1 expression in macrophages antagonizes cytotoxic T-cell attraction and enhances angiogenesis in vitro. Together, this study uncovers CUX1 as an important modulator of the macrophage phenotype and function via modulating of NF-κB dependent gene expression. This knowledge might contribute to a better understanding of the molecular mechanisms underlying the tumor-promoting effect of macrophages and to novel therapeutic approaches.