Significance and Molecular Regulation of Lymphangiogenesis in Cancer

Lymphatic dissemination of tumor cells involves invasion into tumor-associated lymphatic vessels, seeding of metastases in the lymph nodes, and, ultimately, delivery into the blood circulation and to distant organs. Tumor lymphangiogenesis is induced by factors released by tumor or stromal cells, such as macrophages, and facilitates metastasis by providing pathways for cancer cell spread. Vascular endothelial growth factors VEGF-C and VEGF-D are the most specific lymphangiogenic factors that mediate signals for lymphatic endothelial cell growth and migration by binding to and activating VEGFR-3 receptors. Extensive preclinical data in mouse tumor models with specific inhibitors of lymphangiogenic signaling pathways provided the impetus for clinical trials of such agents in patients. In clinical practice, the presence of tumor cells in sentinel lymph nodes is an adverse prognostic factor for patients with solid tumors and constitutes a major consideration in tumor staging. Lymphovascular invasion, lymphatic vessel densities, and the expression of lymphangiogenic factors are also strongly correlated with poor prognosis. Although lymphatic and blood vascular endothelium share many molecular features, they are structurally and functionally distinct and play very different roles in tumors. Here, we discuss the distinct functions and significance of the lymphatic vascular system in cancer.