Integrin α4β1/VCAM-1 pathway mediates primary adhesion of RAW117 lymphoma cells to hepatic sinusoidal endothelial cells under flow
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Adhesion and stabilization of circulating tumor cells to endothelial cells in target blood vessels play an important role in the complex process of metastasis. We examined the cell surface receptors involved in the liver-metastatic 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 and PECAM-1 are constitutively expressed on the surfaces of both HSE and RAW117 cells. However, monoclonal antibody (mAb) blockade studies showed that ICAM-1 and PECAM-1 affected neither the attachment nor the stabilization step of the adhesion of RAW117 cells to HSE cell monolayers under flow. In contrast, RAW117 cells required a significantly lower shear stress to establish adhesion to HSE cells when VCAM-1 receptors on HSE cells were blocked with mAb. Furthermore, the presence of the anti-VCAM-1 mAb significantly decreased the extent of adhesion compared to that of the control, without affecting adherent cell stabilization times. Blocking the α4integrin subunits present mainly on RAW117 cells produced similar results to those previously observed with anti-VCAM-1 mAb. Although constitutively present mainly on the surfaces of RAW117 cells, MAdCAM-1 and β7 integrin subunit do not appear to play a role in either the arrest or stabilization of RAW117 cells on HSE cell monolayers. However, blocking the β1integrin subunit on the RAW117-H10 cells reduced adhesion to the same extent as anti-α4 and anti-VCAM-1 treatments. These observations suggest that an interaction of integrin α4β1on RAW117 cells with liver endothelial VCAM-1 occurs during the early stages of the adhesion process and may be important in liver metastasis.
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