Figure 15. Schematic representation of the cross talk between tumor cells and lymphatic endothelial cells:

(A) In autocrine regulation, VEGF-D produced by 468LN breast cancer cell line binds to α9β1 integrin cell surface receptor to induce the migration and invasion of cancer cell via Erk signaling. (B) In paracrine regulation, VEGF-D secreted by 468LN cells binds to VEGF-R3 on lymphatic endothelial cell (LEC) surface and induces migration and tube formation by the LEC via Erk signaling. (C) Binding of VEGF-D to α9β1 integrin located on the cancer cell membrane still leaves its binding site for VEGF-R3 located on the LEC membrane unoccupied. This leads to dual signaling by this ligand for both tumor and endothelial cells in a highly localised manner, defined as juxtacrine regulation.