Figure 4.

A proposed paracrine loop to establish pre‐metastatic microenvironment in lungs. Ephrin‐A1 expression is enhanced by the TLR4/S100A8 axis. ADAM12 is up‐regulated by inflammatory cytokines such as TNFα and TGF‐β1. Cleaved ephrin‐A1 enters into blood stream and stimulates lung vascular endothelial cells leading to an elevation of CCL2 secretion. The CCR2/CCL2 axis contributes to an increase of SAA3 and S100A8/S100A9 expression. The paracrine loop increases permeability factors enclosed by red box, and then tumor metastasis are facilitated in the lungs. Up‐regulated S100A8/A9 expression in endothelial cells and leukocytes may increase ephrin‐A1 expression mediated by TLR4 and/or EMMPRIN in primary tumors