The homing and mobilization mechanisms of bone marrow derived cells and the involvement in tumor growth
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Nowadays, it is widely accepted that angiogenesis plays a major role in tumor growth. Angiogenesis is required for invasive tumor growth and metastasis formation. Avascular tumors are restricted in their growth potential because of the lack of blood supply. For tumors to growth and metastasize they must make an "angiogenic switch". This can occur by sprouting of pre-existing blood vessel and endothelial cell migration, which is called angiogenesis, or de novo vessel formation by recruitment of specific bone marrow derived cells (BMDCs), which is called vascularization. The switch from hypoxia to blood vessel formation is regulated by several pro-angiogenic factors and the recruitment of BMDCs. Especially endothelial progenitor cells (EPCs) and haematopoietic progenitor cells (HPCs) seem to play an important role in tumor growth and angiogenesis. EPCs and HPCs are suggested to establish a favorable tumor microenvironment by secreting pro-angiogenic factors. Furthermore tumor associated macrophages, mesenchymal cells, carcinoma-associated fibroblasts and pericytes are important in supporting the tumor microenvironment. The recruitment of BMDCs first involves the detachment from the BM stromal cells followed by the homing to a specific site. BMDCs are homed to the tumor via the up-regulation of various factors like, the transcription factor HIF1, the growth factors FGF, VEGF, PlGF, G-CSF and the chemokines SDF1, MCP1 and RANTES. Also the nervous system is suggested to be involved in BMDC mobilization. Especially in a stress situation, like rapid tumor growth and treatment with chemotherapy or surgery, BMDCs seem to play an important role. By unraveling the role and the homing mechanisms of BMDCs in tumor growth, promising anti-tumor therapies might be revealed. Therefore, this thesis will focus on the role of BMDCs in tumor growth and the factors involved in the homing and mobilization of these BMDCs. Furthermore it will focus on the effect of present anti-tumor therapies on BMDCs and how these therapies can be adjusted to enhance their efficiency.