IL-1-ALPHA GENE-TRANSFECTED HUMAN-MELANOMA CELLS INCREASE TUMOR-CELL ADHESION TO ENDOTHELIAL-CELLS AND THEIR RETENTION IN THE LUNG OF NUDE-MICE

The interleukin-1 alpha (IL-1) gene was introduced by retroviral gene transfer into the A375P human melanoma cell line. Two hygromycin-resis tant colonies, colony 3 and colony 6, which respectively do not and do express and release IL-1, were selected on the basis of Northern blot and ELISA. Both colonies adhered to resting human endothelial cells ( EG) to the same extent. Pre-treatment of EG for 6 hr with conditioned medium (GM) from colony 6, but not from colony 3, increased the adhesi on of A375P melanoma and HT-29 colon-carcinoma cells to EC. This incre ase was blocked by adding interleukin-1-receptor antagonist (IL-1ra) t o the EG monolayer. Treatment of EC with colony-6-CM increased the exp ression of intercellular-adhesion molecule 1 (IGAM-1), vascular-cell-a dhesion molecule (VGAM-1) and E-selectin. Co-cultivation of colony-6 b ut not colony-3 melanoma cells with EC caused time-dependent increased expression of these adhesion proteins, reflecting their kinetics of e xpression on EG. Treating the EC with monoclonal antibodies to VGAM-1 and E-selectin abolished the colony-6-CM-induced increase in adhesion respectively to A375P melanoma and HT-29 colon-carcinoma cells. In viv o, i.v. injection of colony-6 cells in nude mice increased the express ion of VGAM-1 on lung microvascular EC. The retention of radiolabeled A375P melanoma cells in the lung was increased in nude mice primed wit h colony-6 cells, but not with colony-3 cells, injected 6 hr earlier. These results demonstrate that IL-1 produced constitutively by transfo rmed A375P melanoma cells is functionally active, inducing adhesion mo lecules on EG that enhance their adhesiveness for tumor cells and incr ease tumor-cell retention in the lung of nude mice.