Hydrogen peroxide mediates vascular cell adhesion molecule-1 expression from interleukin-18-activated hepatic sinusoidal endothelium: Implications for circulating cancer cell arrest in the murine liver

The mechanism of intrasinusoidal arrest of circulating cancer cells, which is a critical step in liver metastasis, appears to be facilitated by tumor- derived proinflammatory factors that increase sinusoidal cell adhesion rece ptors for cancer cells. However, how this prometastatic microenvironment is up-regulated remains unknown. Using intrasplenically injected B16 melanoma (B16M) cells, we show that the expression of vascular cell adhesion molecu le-1 (VCAM-1) significantly increased in hepatic sinusoidal endothelium (HS E) cells over physiologic baseline within the first 24 hours of metastatic cancer cell infiltration in the liver. This correlated with increased in vi tro adhesion of B16M cells to HSE cells isolated from B16M cell-injected mi ce. In vivo VCAM-1 blockade with specific antibodies before B16M cell injec tion decreased sinusoidal retention of luciferase-transfected B16M cells by 85%, and metastasis development by 75%, indicating that VCAM-1 expression on tumor-activated HSE cells had a prometastatic contribution. Because VCAM -1 expression is oxidative stress-inducible, recombinant catalase was in vi vo administered, resulting in a complete abrogation of both VCAM-1 expressi on and B16M cell adhesion increases in HSE cells isolated from B16M cell-in jected mice. Catalase also abrogated the proadhesive response of HSE cells to B16M-conditioned medium (B16M-CM) in vitro, although this did not affect the concomitant release of major proinflammatory cytokines by HSE cells. H SE cells treated with B16M-CM released interleukin (IL)-18 via tumor necros is factor-alpha (TNF-alpha)- dependent IL-1 beta in vitro. In turn, H2O2 pr oduction from B16M-CM-treated HSE cells was regulated by IL-18. Thus, liver -infiltrating B16M cells activated their adhesion to HSE through a sequenti al process involving TNF-alpha -dependent IL-1 beta, which induced IL-18 to up-regulate VCAM-1 via H2O2. The pivotal position of H2O2 was further supp orted by the fact that incubation of HSE cells with nontoxic concentrations of H2O2 directly enhanced VCAM-1-dependent B16M cell adhesion in vitro wit hout proinflammatory cytokine mediation, which emphasizes the key role of o xidative stress in the pathogenesis of liver inflammation and metastasis.