Fig. 1

The structure of lymphatic system and tumor-associated lymphatic metastasis in NSCLC. (A) Initial lymphatic vessel (LV) is lined by a single layer of LECs without a continuous basement membrane to uptake ISF and macromolecules by the blood vessels. LECs produce the chemokine gradients of CCL21 to entry immune cells expressing CCR7 into initial LV. (B) The lymphatic flow reaches TDLN though afferent LV, where the lymph permeates in subcapsular and medullary sinuses and eventually come into the efferent LV. Tumor cells, leukocyte, migratory dendritic cells (DCs), antigens, tumor-derived secreted factors (TDSFs), and tumor-derived extracellular vesicles (EVs) drain the subcapsular sinuses (SCS). Newborn LECs create and maintain chemokine gradients that direct DC migration. And CD169 + SCS macrophages capture tumor-derived material for antigen presentation. These culminate a pre-micrometastasis niche that crosses metastasis and immunity supporting tumor cell proliferation, adhesion, invasion, and LN immune suppression. (C) Various cells, including tumor cells, secrete growth factors to activate receptors on the LEC surface to regulate LEC growth and migration and remodel LV networks. Lymphangiogenesis-mediating receptors involve ligands or interacting proteins, homologous receptors, and specific LECs markers