Fig. 2.

Establishment of the lymph node (LN) pre-metastatic niche. Tumor-derived factors, including vascular endothelial growth factor (VEGF-A, VEGF-C and VEGF-D), extracellular vesicles, TGF-β and lysyl oxidase (LOX), induce an immunosuppressive microenvironment by recruiting macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Proliferation of lymphatic endothelial cells (LECs) and fibroblastic reticular cells (FRCs) drives the production of LN factors such as chemokines (CCL19; CCL21; CXCL1, 2, 5, 8, and 12); TGF-β; matrix metalloproteinases (MMPs); indoleamine-2,3-dioxygenase (IDO); and nitric oxide (NO), which induce high endothelial venule (HEV) remodeling, stimulate lymphangiogenesis, and regulate tumor cells chemoattraction at metastatic stage