INCREASED PLASMINOGEN-ACTIVATOR AND TYPE-IV COLLAGENASE ACTIVITY IN INVASIVE FOLLICULAR THYROID-CARCINOMA CELLS

Background. An essential difference between benign and malignant folli cular thyroid tumors is the ability to invade and metastasize. Thyrotr opin (TSH) stimulates invasion of cultured human follicular thyroid ca ncer cells (FTC-133) via a protein Kinase C (PKC) dependent mechanism. Tumor invasion depends on degradation of extracellular matrix by prot eases. Methods. We analyzed protease activity in FTC-133 and its more invasive clone, FTC-238. Cells were treated with TSH or 12-0-tetradeca noyl-phorbol-13-acetate (TPA), a PKC agonist, for 24 hours. Conditione d medium and cellular extract were subjected to substrate gel zymograp hy with either casein-plasminogen or gelatin (collagen). Western blot and immunohistochemistry confirmed protease identity. Results. We foun d increased 50 kd urokinase-like plasminogen activator (uPA) and 62 kd gelatinase activity by FTC-238 cells compared with the less invasive FTC-133 cells. There was no effect of TSH on uPA or collagenase activi ty at concentrations of 0.01 to 10 mU/ml. In both FTC-133 and FTC-238, TPA incubations of 0.1 to 100 ng/ml caused a dose-dependent increase in uPA and a 94 kd type IV collagenase. Conclusions. These findings sh ow that TSH-stimulated invasion may be due to PKC-induced activation o f uPA and 94 kd type IV collagenase, uPA and basement membrane type IV collagenase warrant investigation as markers for follicular thyroid c ancer.