Embryonic and tumor-induced lymphangiogenesis

For more than a years the embryonic development of the lymphatic vascular system has been studied, but there is still debate about its origin from specific segments of the venous system or from mesenchymal lymphangioblasts. Recent studies have shown that normal development of veins is indispensable for development of lymphatic endothelial cells (LECs). Early embryonic lymph sacs develop by transdifferentiation from venous ECs. However, the question remains if mesenchymal cells integrate into the growing lymphatic system. Our grafting experiments on avian embryos show that numerous mesenchymal compartments have the capacity to form LECs, which integrate into the lymphatic endothelium. In murine embryos we observed cells that combine lymphendothelial and macrophage characteristics. We assume that such highly mobile cells are also present in humans, and are probably the cell of origin of Kaposi’s sarcoma.

In addition, the role of circulating cells in tumor-induced lymphangiogenesis has remained unknown. We have been the first to show by grafting of tumor cells on the avian chorioallantoic membrane that there is Vascular Endothelial Growth Factor-C (VEGF-C)-induced tumor lymphangiogenesis. A positive correlation between VEGF-C-expression on lymph node metastases has been described frequently in recent years. We are now characterizing lymphangioblasts in the human and search for molecules, which inhibit lymphangiogenesis. Such molecules might be of therapeutic relevance in lymphangioma, a benign hyperplasia of the lymphovascular system. We have shown that VEGFR-3, the high affinity receptor for VEGF-C and -D, is up-regulated in LECs in lymphangioma patients. Preliminary in vitro studies have already been performed successfully.