Lymphangiogenesis: Lymphatic System and Lymph Nodes; Cancer Lymphangiogenesis and Metastasis

The lymphatic system is considered the major conduit for cancer metastasis. Two key recent developments have made cancer lymphangiogenesis and cancer metastasis more understandable on a molecular and translational level. These include the discovery of lymphatic markers such as VEGF-C, LYVE-1, podoplanin, and Prox-1 and the recognition of the clinical significance of sentinel lymph nodes (SLNs) in melanoma and breast cancer. The lymphatic system develops during the fifth week of embryological life based on Sabin’s centrifugal theory and on a minor extent relating to contrasting centripetal theory. The extracellular fluid that escapes at the blood capillaries is absorbed through the lymphatic vessels and passes through multiple levels of lymph nodes. The lymph from most of the body subsequently drains in a large part into the thoracic duct and then to the left subclavian vein. On the upper right side of the body, drainage is largely into the right subclavian vein. Thus, the excess extracellular fluid transported as lymph through the lymphatic vessels and filtered through the lymph nodes becomes sterile from bacteria or other microorganisms prior to reentry into the circulatory system. Although cancer angiogenesis involving blood vessels (hemangiogenesis) occurs in the tumor microenvironment, its prognostic value is unclear. On the other hand, cancer lymphangiogenesis has been extensively studied and it is associated significantly with poor prognosis. Cancer cells in the primary tumor site have the propensity to migrate to the SLN of the tumor draining nodal basin, then, to distant sites. Occasionally, cancer cells may escape into the blood vessels for distant metastasis. In general, the SLN may be considered as the major gateway for cancer metastasis. Micrometastasis in the SLN is an excellent biomarker for a poor clinical outcome. Based on experimental and clinical evidence, the SLN may be preconditioned by factors produced by cancer cells in the primary site to form a pre-metastatic niche that facilitates the arrival of cancer cells to take residence in the SLN. Molecular mechanisms of how cancer cells dissociate from the primary site, follow the lymphatic vessels to reach the SLN, and then, spread beyond to the distant sites remain under investigation.