INVOLVEMENT OF INTEGRIN ALPHA(V)BETA(3) IN CELL-ADHESION, MOTILITY, AND LIVER METASTASIS OF MURINE RAW117 LARGE-CELL LYMPHOMA

The molecules that mediate metastatic cell homing to specific organ si tes remain largely unidentified. As a target organ for metastasis, the liver is a unique environment characterized by fenestrated sinusoidal endothelium, lack of a complete basement membrane, and production of serum components, including fibronectin and vitronectin. We examined a series of murine RAW117 large cell lymphoma variants selected in vivo for liver-colonizing properties (H10 >> L17 > P). Compared with L17 o r P cells, the highly liver-colonizing H10 cells expressed much higher levels of surface integrin alpha(v) beta(3), as shown by affinity chr omatography, immunoprecipitation, and flow cytometry. H10 cells adhere d at higher rates to vitronectin and fibronectin than to fibrinogen, f ibrin, laminin, and type I collagen. Among the RGD) peptides, H10 cell s adhered at significantly higher rates to the polymeric RGD peptide ( glycyl-arginyl-glycyl-aspartyl-serine), than to monomeric RGD peptides . H10 cells were able to spread on immobilized vitronectin with highly polarized morphology but not on fibronectin. In contrast, the poorly liver-metastatic P and L17 cells did not adhere or spread well on vitr onectin or fibronectin. H10 cells also migrated toward vitronectin con centration gradients. Blocking cell surface alpha(v) beta(3), molecule s with specific anti-beta(3) monoclonal antibodies resulted in signifi cant decreases in the adhesion of H10 cells to vitronectin and (glycyl -arginyl-glycyl-aspartyl-serine), and significant inhibition of the fo rmation of experimental liver metastases. These data suggest an import ant role of integrin alpha(v) beta(3) in the metastasis of RAW117 cell s to the liver.