Integrin alpha(4)beta(1)/VCAM-1 pathway mediates primary adhesion of RAW117 lymphoma cells to hepatic sinusoidal endothelial cells under flow

Adhesion and stabilization of circulating tumor cells to endothelial cells in target blood vessels play an important role in the complex process of me tastasis. We examined the cell surface receptors involved in the liver-meta static adhesive interactions of murine RAW117 large-cell lymphoma cells to unstimulated hepatic sinusoidal endothelial cells (HSE) under physiological flow conditions. Flow cytometric analysis indicated that VCAM-1, ICAM-1 an d PECAM-1 are constitutively expressed on the surfaces of both HSE and RAW1 17 cells. However, monoclonal antibody (mAb) blockade studies showed that I CAM-1 and PECAM-1 affected neither the attachment nor the stabilization ste p of the adhesion of RAW117 cells to HSE cell monolayers under flow. In con trast, RAW117 cells required a significantly lower shear stress to establis h adhesion to HSE cells when VCAM-1 receptors on HSE cells were blocked wit h mAb. Furthermore, the presence of the anti-VCAM-1 mAb significantly decre ased the extent of adhesion compared to that of the control, without affect ing adherent cell stabilization times. Blocking the alpha(4)integrin subuni ts present mainly on RAW117 cells produced similar results to those previou sly observed with anti-VCAM-1 mAb. Although constitutively present mainly o n the surfaces of RAW117 cells, MAdCAM-1 and beta(7) integrin subunit do no t appear to play a role in either the arrest or stabilization of RAW117 cel ls on HSE cell monolayers. However, blocking the beta(1)integrin subunit on the RAW117-H10 cells reduced adhesion to the same extent as anti-alpha(4) and anti-VCAM-1 treatments. These observations suggest that an interaction of integrin alpha(4)beta(1)on RAW117 cells with liver endothelial VCAM-1 oc curs during the early stages of the adhesion process and may be important i n liver metastasis.