Cytokines modulate in vitro invasiveness of renal cell carcinoma cells through action on the process of cell attachment to endothelial cells.

Cytokines play important roles in adhesion between various cells and endothelium. Cell-cell adhesion is also a critical step in the invasion of interstitial tissue by cancer cells. Using an in vitro invasion assay modified by cultured human umbilical venule endothelial cells (HUVEC) and an extracellular matrix (Matrigel) membrane system, we studied how cytokines affect the invasiveness of human renal cell carcinoma cells through action on the endothelium. When HUVEC were treated for 6 hours with tumor necrosis factor (TNF, 100 or 1000 U/ml.), interleukin-1 (IL-1, 10 ng./ml.) or IL-6 (1.0 or 10 ng./ml.), the treatment significantly increased in vitro invasiveness of the carcinoma cells. Enhancement of carcinoma cell invasiveness reflected the enhancement by the cytokine treatments of the ability of HUVEC to express vascular cell adhesion molecule-1 (VCAM-1). Application of anti-VCAM-1 monoclonal antibody (mAb) suppressed in vitro invasion of the carcinoma cells when HUVEC were treated with the cytokines at the above concentrations. Moreover, an adherence assay demonstrated that a larger number of carcinoma cells adhered to the endothelium treated by the cytokines than to endothelium not receiving such treatment and that anti-VCAM-1 mAb application inhibited the adhesion. The cytokine treatment of HUVEC did not affect type IV collagenolysis. These results indicated that cytokines can enhance the in vitro invasiveness of carcinoma cells through their action on endothelium (that is, augmentation of VCAM-1 expression) in the in vitro invasion assay modified with HUVEC-Matrigel-reconstituted membrane.