Molecular regulation of lymphangiogenesis in development and tumor microenvironment.

A rapid progress has been made in the field of lymphatic research during the last 15 years. This includes better understanding of the cellular events and molecular players involved in the lymphatic vessel formation and remodeling in development. The key players identified in developmental lymphangiogenesis, including vascular endothelial cell growth factor-C (VEGF-C) / VEGFR-3 and angiopoietins (ANGPTs)/ TIE pathways, are also crucial for pathological lymphatic vessel growth. In solid tumor, tumor cells as well as tumor-associated stromal cells, such as tumor-infiltrating leukocytes, contribute to intra- and peri-tumoral lymphangiogenesis via secreting lymphangiogenic growth factors. Tumor-associated lymphatic endothelial cells also interact actively with tumor cells and leukocytes via secreting various chemokines. It has been well established that tumor lymphangiogenesis promotes tumor cell dissemination to regional lymph nodes. Thus manipulation of lymphangiogenic microenvironment could become another valuable approach in the combat of tumor progression.