Tumor cell adhesion to endothelial cells is increased by endotoxin via an upregulation of beta-1 integrin expression

Background. Recent studies have demonstrated that metastatic disease develo ps from tumor cells that adhere to endothelial cells and proliferate intrav ascularly. The beta -1 integrin family and its ligand laminin have been sho wn to be important in tumor-to-endothelial cell adhesion. Lipopolysaccharid e (LPS) has been implicated in the increased metastatic tumor growth that i s seen postoperatively. We postulated that LPS increases tumor cell express ion of beta -1 integrins and that this leads to increased adhesion. Methods. The human metastatic colon cancer cell line LS174T was labeled wit h an enhanced green fluorescent protein (eGFP) using retroviral transfectio n. Cell cultures were treated with LPS for 1, 2, and 4 h (n = 6 each) and w ere subsequently cocultured for 30 or 120 min with confluent human umbilica l vein endothelial cells (HUVECs), to allow adherence. Adherent tumor cells were counted using fluorescence microscopy. These experiments were carried out in the presence or absence of a functional blocking beta -1 integrin m onoclonal antibody (4B4). Expression of beta -1 integrin and laminin on tum or and HUVECs was assessed using how cytometric analysis. Tumor cell NF-kap paB activation after incubation with LPS was measured. Results. Tumor cell and HUVEC beta -1 integrin expression and HUVEC express ion of laminin were significantly (P < 0.05) enhanced after incubation with LPS. Tumor cell adhesion to HUVECs was significantly increased. Addition o f the <beta>-1 integrin blocking antibody reduced tumor cell adhesion to co ntrol levels. LPS increased tumor cell NF-kappaB activation. Conclusions. Exposure to LPS increases tumor cell adhesion to the endotheli um through a beta -1 integrin-mediated pathway that is NF-kappaB dependent. This may provide a target for immunotherapy directed at reducing postopera tive metastatic tumor growth. (C) 2001 Academic Press.