|dc.description.abstracteng||Metastases are a major cause of morbidity and mortality in breast cancer patients. However, current treatments are of limited efficiency because so far very little is known about the colonisation of breast cancer cells into the metastatic organs, in particular the brain. It has been demonstrated that epithelial to mesenchymal transition (EMT) facilitates tumour metastasis with poor prognosis. Moreover, the tumour cell progression might properly be dynamic: EMT during invasion and a reversal (MET) during growth of metastasis. Consequently, EMT and MET might be a promising target as a possible therapeutic cancer treatment. Therefore, the aim of this study was to establish a syngeneic mouse model to investigate the colonization at the distant organs, in this case the brain, of metastatic breast cancer cells and the impact of EMT and MET on this part during the metastasis process.
Furthermore, it has been demonstrated that dysregulation of Wnt signalling is associated with metastasis and also plays an important role in tumour genesis. Furthermore, the Wnt signalling pathway is known to induce EMT and MET and is dysregulated in several cancers, with different Wnt molecules being up regulated. If the Wnt pathway is important in cancer proliferation and metastasis, inhibitors of Wnts may be valuable for a therapeutic strategy. However, because of the multiple receptor combinations and no-central kinase activity the inhibition of the Wnt pathway is not trivial. Therefore, to inhibit the secretion of the Wnt-molecules seemed a very promising strategy. One of the key enzymes during secretion is the membrane bound O-acetyltransferase Porcupine. Inhibition of Porcupine leads to the inhibition of Wnt palmitoylation and Wnt secretion, and therefore, indirect inhibition of receptor binding and activation of the pathway. One Porcupine inhibitor, LGK974, is believed to block initiation of tumours through this mechanism suggesting LGK974 is a good treatment approach for cancer patients. The second aim of this study was now to investigate the inhibitory effects of LGK974, not in tumour initiation, we wanted to study the effect during cerebral colonization in vitro and in vivo.
Finally, we wanted to investigate the role of the immune system, microglia and astrocytes, during the invasion of breast cancer in the brain. The established immune-competed mouse model provides an opportunity to address this question. Here, the response of microglia and astrocytes to lipopolysaccharide (LPS) was used to trigger an immune response.
In conclusion, a syngeneic cerebral metastasis mouse model was established and different treatment strategies were proved on this. Moreover, the process of colonization of the brain, and the impact of the immune systems on in this progress were investigated.||de