E-selectin is a cytokine-inducible endothelial cell adhesion receptor which is involved in the process of leukocyte rolling, the first in a cascade of interactions leading to leukocyte transmigration. Several studies have implicated this receptor in carcinoma cell adhesion to the endothelium, an interaction thought to be required for tumor extravasation during metastasis. To study the role of this receptor in the process of metastasis, we utilized a murine carcinoma line H-59 which is highly metastatic to the liver in vivo. When adhesion of H-59 cells to primary cultures of murine hepatic endothelial cells was measured, it was found that the tumor cells had a low basal level of adhesion to the sinusoidal endothelial cells, which could be significantly and specifically augmented by pre-activation of the endothelial cells with rTNFa. This incremental increase in adhesion to the activated endothelium could be completely and specifically abolished by a neutralizing monoclonal antibody to murine E-selectin (MAb 9A9). Similar results were obtained with 2 highly metastatic human colorectal carcinoma lines, HM 7 and CX-1, but not with a second murine subline, M-27, which is poorly metastatic to the liver. To assess the role of E-selectin in metastasis to the liver in vivo, the effect of MAb 9A9 on experimental liver metastasis was evaluated using the syngeneic H-59 model. We show here that this antibody caused a marked, specific and Fc-independent inhibition of experimental liver metastasis, reducing the median number of metastases by 97% relative to the control groups. Our results provide evidence that endothelial E-selectin is a mediator of carcinoma metastasis to the liver. Int. J. Cancer 71:612-619, 1997.r 1997 Wiley-Liss, Inc.The ability of disseminating cancer cells to establish metastases in secondary organs is regulated by a combination of factors, including access to the organ microvasculature (hemodynamic factors) and specific host-tumor cell interactions (Radinsky and Fidler, 1992). The attachment of circulating tumor cells to the vascular endothelium of the target organ is thought to be one key step in the metastatic cascade. The evidence suggests that this attachment precedes and is required for tumor cell extravasation and subsequent invasion into the target organ parenchyma (Brodt, 1996). Organ-specific receptors have been identified on the luminal surface of the microvascular endothelium which are specifically recognized by tumor cell ligands, thereby facilitating tumor cell arrest and transmigration into the extravascular space (Pauli et al., 1992). Studies of leukocyte transmigration have suggested that the specificity of the interaction between a circulating leukocyte and the microvascular endothelium may be determined by the outcome of a series of sequential receptor-ligand interactions rather than the complementarity of a single receptor-ligand system (Springer, 1994). It appears likely that the process of tumor extravasation is also mediated through a series of adhesive interactions (reviewed in B...