The molecules that mediate metastatic cell homing to specific organ sites 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 or P cells, the highly liver-colonizing H10 cells expressed much higher levels of surface integrin αvβ3, as shown by affinity chromatography, immunoprecipitation, and flow cytometry. H10 cells adhered at higher rates to vitronectin and fibronectin than to fibrinogen, fibrin, laminin, and type I collagen. Among the RGD peptides, H10 cells adhered at significantly higher rates to the polymeric RGD peptide (glycyl-arginyl-glycyl-aspartyl-serine)4 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 vitronectin or fibronectin. H10 cells also migrated toward vitronectin concentration gradients. Blocking cell surface αvβ3 molecules with specific anti-β3 monoclonal antibodies resulted in significant decreases in the adhesion of H10 cells to vitronectin and (glycyl-arginyl-glycyl-aspartyl-serine)4 and significant inhibition of the formation of experimental liver metastases. These data suggest an important role of integrin αvβ3 in the metastasis of RAW117 cells to the liver.
This work was supported by NIH National Cancer Institute Grant CA44352 (G. L. N.) and NIH Core Grant CA 16672.