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 receptors 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 molecule-1 (VCAM-1) significantly increased in hepatic sinusoidal endothelium (HSE) cells over physiologic baseline within the first 24 hours of metastatic
cancer cell infiltration in the liver. This correlated with increased in vitro adhesion of B16M cells to HSE cells isolated from B16M cell-injected mice. In vivo
VCAM-1 blockade with specific
antibodies before B16M cell injection 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 vivo administered, resulting in a complete abrogation of both
VCAM-1 expression and B16M cell adhesion increases in HSE cells isolated from B16M cell-injected 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. HSE cells treated with B16M-CM released
interleukin (IL)-18 via
tumor necrosis factor-alpha (
TNF-alpha)-dependent IL-1beta in vitro. In turn, H(2)O(2) production from B16M-CM-treated HSE cells was regulated by
IL-18. Thus, liver-infiltrating B16M cells activated their adhesion to HSE through a sequential process involving
TNF-alpha-dependent IL-1beta, which induced
IL-18 to up-regulate
VCAM-1 via H(2)O(2). The pivotal position of H(2)O(2) was further supported by the fact that incubation of HSE cells with nontoxic concentrations of H(2)O(2) directly enhanced VCAM-1-dependent B16M cell adhesion in vitro without proinflammatory
cytokine mediation, which emphasizes the key role of oxidative stress in the pathogenesis of liver
inflammation and
metastasis.