Cancer Metastasis: The Lymphatics: On the Route to Cancer Metastasis

The blood vascular and lymphatic systems are necessary for the flux of gases, liquids, nutrients, signaling molecules, and cells among tissues and organs. These two highly branched, treelike networks are interconnected through the largest lymphatic vessel, the thoracic duct, which drains lymph, the protein-rich interstitial fluid, into the blood circulation. Both networks contribute to homeostasis of a healthy individual, and their malformation or dysfunction contributes to the pathogenesis of many diseases, such as cancer [1]. The lethality of cancer is associated primarily with metastasis – that is, the spread of cancer cells from the primary site to lymph nodes and to distant organs [2]. In principle, tumor cells can spread within the body by three main pathways: direct invasion of surrounding tissues, via the blood system to distant organs (hematogenous spread), or via the lymphatic system to the sentinel lymph node, distal lymph nodes, and distant organs (lymphogenous spread) (Figure 22.1). Tumor cells induce the growth of new lymphatic vessels within and immediately around tumors and draining lymph nodes, enhancing immune cell trafficking to lymph nodes. Increased lymphatic vessel density in tumors is also associated with increased metastasis to lymph nodes [3]. The extent of lymph node metastasis is a major determinant for disease staging. Despite its clinical relevance, however, little is known about the mechanisms that govern spread via the lymphatic system.