Uncovering triggers of colonization in brain metastasis
by Raquel Blazquez
Date of Examination:2017-01-24
Date of issue:2017-04-26
Advisor:Prof. Dr. Tobias Pukrop
Referee:Prof. Dr. Heidi Hahn
Referee:Prof. Dr. Peter Burfeind
Persistent Address:
http://dx.doi.org/10.53846/goediss-6264
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Abstract
English
Brain metastases (BM) are frequent in cancer patients and are associated with poor prognosis. The incidence of BM is increasing mainly due to an improved control of primary tumors and an increased median survival of the patients. However, only limited treatment strategies are available nowadays. From a biological point of view, metastases are highly inefficient. Recent studies point out the colonization as the bottleneck of this process. Moreover, the colonization of the target organ seems to be the only targetable event to stop brain metastasis. However, although much effort has been made during recent years to understand the first steps of the metastatic cascade, the colonization of the target organ remains unexplored. Therefore, we aimed to investigate the mechanisms underlying this process and looked for triggers of colonization during brain metastasis. By means of a new quantification tool, the Colonization Index, the breast cancer cells 4T1 were found to have a higher colonization potential than the parental 410.4 in our brain colonization in vivo models. The expression of the mesenchymal marker vimentin seemed to confer certain plasticity to the cellular architecture, which in turn promoted a better colonization of the brain parenchyma by the tumor cells without the loss of their fundamental epithelial phenotype. Therefore, we propose the acquisition of mesenchymal features by the tumor cells as a feasible trigger of colonization during brain metastasis. Moreover, the present work underlies once again the importance of the tumor microenvironment in supporting metastasis formation, and proposes the PI3-kinase as a feasible therapeutic target for the treatment of this devastating illness. Here, we demonstrate that BKM120 can effectively block the PI3K/Akt signaling pathway, and consequently blunts the innate pro-tumorigenic activity of tumor-associated macrophages into a tumor-suppressing phenotype. This phenotypic change is driven by the modulation of the myeloid transcription factor PU.1 in the metastatic tissue, and results in prolonged overall survival. We propose that such macrophage-re-educating agents in combination with immunotherapy may constitute a promising therapeutic option for patients suffering from BM. In conclusion, our data emphasize once again the complexity of metastasis. In this work, both the acquisition of metastatic traits by tumor cells, as well as the tumor promoting role of the surrounding stromal cells were identified as feasible triggers of brain colonization.
Keywords: Brain metastasis; Macrophages; Colonization; PI3K; CSF1R; Breast cancer
