New Insights into the Molecular Mechanisms of Lymphangiogenesis and Pathophysiology

Lymphatic vessels play crucial roles in transporting tissue fluid and macromolecules, and in promoting tissue immune response. Recent studies have identified new lymphatic vessel growth in pathological conditions such as cancer progression. In fact, our experimental animal models revealed that tumors can induce lymphangiogenesis not only in primary sites, but in their draining lymph nodes (LNs), even before tumors get metastasized. In fact, lymphangiogenesis in draining lymph nodes leads to increased cancer spread to distant LNs and beyond. Importantly, we very recently identified that nodal lymphangiogenesis occurs in human skin cancers, and plays a significant role in promoting distant metastases resulting in reduced patient survival. Therefore, lymphangiogenesis could be a novel indicator and therapeutic target for the prevention of cancer metastasis. Recent advances in clarifying the functional role of lymphatic vessels began with the molecular identification of genes which are specifically expressed by the lymphatic endothelial cells. Lymphatic vessels arise from veins. Prox1, a homeobox transcription factor, specifies the lymphatic identity from venous endothelial cells. Thus, Prox1 is a master regulator of lymphatic vessel development. Vascular endothelial growth factor-C and its specific receptor VEGFR-3 compose an essential signal pathway for lymphatic vessel growth in physiological and pathological conditions. Furthermore, podoplanin, another transmembrane protein in lymphatic vessels is required for their separation from veins by activating CLEC2, the specific ligand in platelets, leading to thrombus formation between veins and lymphatic vessels. Moreover, recent progress in nano-scale technologies enabled to visualize lymphatic vessels and quantitate their transport, leading to new approaches for nano-based medicine.