Despite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our... Show moreDespite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our understanding of metastasis formation remains a challenge for further drug development. The scope of this thesis is the identification of novel candidate metastasis genes, with a main focus on candidate genes affecting tumor cell migration. For that purpose, a live cell imaging-based random cell migration assay that is suitable for screening has been developed. In addition, a mouse breast cancer model that allows to study tumor cell autonomous processes of metastasis formation is described. A RNA-interference tumor cell migration screen has been done and resulted in the identification of novel regulators of tumor cell migration that show clinical relevance in a breast cancer patient cohort. In addition, focused research has been conducted on two previously identified candidate metastasis genes to determine their role in breast cancer metastasis. Show less
TGF-beta and BMPs are members of the TGF-beta superfamily of cytokines which play an important role in a multitude of processes. In cancer, TGF-beta is known for its dual role: in early stages it... Show moreTGF-beta and BMPs are members of the TGF-beta superfamily of cytokines which play an important role in a multitude of processes. In cancer, TGF-beta is known for its dual role: in early stages it inhibits cancer cell proliferation, whereas in later stages it promotes invasion and metastasis. In this thesis, a 3 dimenstional model to monitor TGF-beta-induced invasion of breast cancer cells is presented and an important role for MMP2 and MMP9. Furthermore, BMP-7 could inhibit TGF-beta-induced invasion through inhibition of TGF-beta-induced integrin beta3 expression. The property of TGF-beta to induce epithelial to mesenchymal transition (EMT) is thought to contribute to its pro-invasive effect. We found that transcription factors involved in this process induce invasion. Lastly, we identified kinases involved in BMP signaling. These findings help the understanding of breast cancer cell invasion and a way to prevent this process. Show less
The aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In... Show moreThe aim of this work was to develop methods to measure structural changes in the skeleton using MicroCT. In addition, these new methods should be able to quantify biologically relevant changes. In order to do this, normalized methods to analyse MicroCT scans and perform quantitative measurements within these datasets are described in this thesis. These techniques were combined with a biological angiogenesis assay and used as research tools in a study comparing various different combination treatments of bone metastases. Show less
