The Formation of Lymphatic Vessels and Its Importance in the Setting of Malignancy

The lymphatic vascular system plays important roles in the maintenance of tissue fluid homeostasis, in the mediation of the afferent immune response, and in the metastatic spread of malignant tumors to regional lymph nodes. It consists of a dense network of blind ending, thin-walled lymphatic capillaries and collecting lymphatics that drain extravasated protein-rich fluid from most organs and transport the lymph via the thoracic duct to the venous circulation (1). Originally discovered as " milky veins " by Gasparo Aselli in the 17th century (2), the mechanisms controlling the normal development of lymphatic vessels and the molecular regulation of their biological function have remained poorly understood in contrast to the rapid progress made in elucidating the formation and molecular control of the blood vascular system (3, 4). 100 yr ago, Florence Sabin proposed that the lymphatic system develops by the sprouting of endothelial cells from embryonic veins, leading to the formation of primitive lymph sacs from which lymphatic endothelial cells then sprout into surrounding organs to form mature lymphatic networks (5, 6). Since these pioneering studies, however, the field of lymphatic research has remained rather neglected , mainly due to the lack of molecular tools to specifically detect and functionally characterize the lymphatic endothelium. The recent identification of several new markers for lymphatic endothelial cells and of lymphatic growth factors and receptors, together with the characterization of genetic mouse models with impaired lymphatic development and/or function, has now led to a " rediscov-ery " of the lymphatic vascular system and has provided important new insights into the molecular mechanisms that control its development and biological function (7). Importantly , these studies have largely confirmed Sabin's original hypothesis regarding lymphatic development in the mamma-lian system (Fig. 1). Recently, Wigle and Oliver (8) and Wigle et al. (9) have identified the first gene that is essential for early lymphatic development. Beginning at E9.5 of mouse development, the homeobox gene Prox1 starts to become specifically expressed in a subpopulation of endothelial cells located on one side of the anterior cardinal vein (8). At this stage, the venous endothelium also expresses the hyaluronan receptor LYVE-1, a CD44 homologue (10), and vascular endothe-lial cell growth factor receptor (VEGFR)-3, a receptor for the lymphangiogenesis factors vascular endothelial growth factor (VEGF)-C and VEGF-D (11). The expression of both of these receptors later becomes restricted to lym-phatic endothelium (Fig. 1; reference 12). This is followed by the polarized …