Cellular and molecular mechanisms of tumor-induced lymphangiogenesis

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Since the description of specific lymphatics markers the role of lymphangiogenesis in cancer research is increasing. We will investigate whether tumor-lymphendothelial interaction induces specific new genes in lymphatic endothelial cells. The used systems will be a murine embryonic stem cell derived embryoid body assay and a new established tumor metastasis model. Previously, the targeting of lymphangiogenesis and angiogenesis was almost exclusively studied in primary tumor models. However, in human patients primary tumors are usually excised and the treatment of metastases represents the most challenging therapeutic problem. To better mimic the human situation, we have to target the lymph node metastasis after the removal of the primary tumor. In a breast carcinoma model we observed, that lymphangiogenesis is increased in the sentinel lymph nodes of VEGF-C expressing MDA tumors compared to control tumors, similar to changes observed in a skin carcinoma model in VEGF-Atransgenic mice and in human melanoma metastasis.1, 2 We will evaluate the upregulation of genes in the tumor associated lymphatic endothelial cells and the influence of blocking antibodies on further cancer spread from the sentinel lymph node. Moreover we will evaluate the impact of these antibodies on the lymph flow inside sentinel and distant lymph nodes. These two systems (in vivo / in vitro) will allow us to define new specific targets and the impact of blocking lymph node lymphangiogenesis on tumor spread.