Role of lymphatic vasculature in regional and distant metastases

Abstract

In cancer, lymphatic vasculature has been traditionally viewed only as a transportation system for metastatic cells. It has now become clear that lymphatics perform many additional functions which could influence cancer progression. Lymphangiogenesis, induced at the primary tumor site and at distant sites, potently augments metastasis. Lymphatic endothelial cells (LECs) control tumor cell entry and exit from the lymphatic vessels. LECs also control immune cell traffic and directly modulate adaptive immune responses. This review highlights advances in our understanding of the mechanisms by which lymphatic vessels, and in particular lymphatic endothelium, impact metastasis.

Keywords: CCL1; CCR8; Chemokine; Immunoregulation; Lymph node; Lymphangiogenesis; Lymphatic endothelium; Metastasis; VEGF-C; VEGFR-3.

Figure 1. Model for tumor cell entry into the lymph node

Prior to the arrival of tumor cells, subcapsular sinus (SCS) dilates starting at the orifice of the afferent lymphatic vessel. Tumor emboli arriving from the afferent lymph first arrest at the junction of the afferent lymphatic vessel and the subcapsular sinus. From here, tumor cells expressing CCR8 migrate laterally into the subcapsular sinuses, guided by the CCL1 chemokine which is presented on the surface of SCS LECs. Single cells and small cell clusters may move with the flow of lymph laterally into the sinus. Within the SCS, tumor cells attach to the floor and the roof of the sinus, where they continue to proliferate. Colonization of the SCS is a first step of lymph node metastasis and it is a result of concurrent migration and growth of tumor cells within the sinus. Next step is tumor cell migration across the floor of the sinus into the LN cortex, process also guided by the CCL1 chemokine presented by SCS LECs.