INACTIVE UROKINASE AND INCREASED LEVELS OF ITS INHIBITOR TYPE-1 IN COLORECTAL-CANCER LIVER METASTASIS

Background/Aims: Human colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activato r expression, both in antigen and activity, accompanied by simultaneou sly enhanced levels of plasminogen activator inhibitors type 1 and typ e 2. This increased proteolytic activity may contribute to invasive gr owth and metastasis of the tumors. Methods: In the present study, homo genates of liver metastases, primary colorectal carcinomas, and adjace nt normal tissues were evaluated regarding the level and composition o f urokinase, tissue-type plasminogen activator, and plasminogen activa tor inhibitors. Results: Concentrations of urokinase were significantl y increased in primary carcinomas and liver metastases compared with n ormal tissues, whereas tissue-type plasminogen activator levels were s ignificantly decreased. Liver metastases showed, in contrast to the ca rcinomas, hardly any activity of plasminogen activators, which could b e attributed to the enhanced presence of the inactive proenzyme form o f urokinase in combination with more complexes of plasminogen activato rs with inhibitors. Furthermore, liver metastases had an eightfold hig her content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen acti vators to metastasis homogenates, which resulted in increased complex formation. Conclusions: Colorectal cancer metastasis in the liver is a ssociated with an inactivation of the enhanced urokinase cascade, whic h might allow tumor cells to settle in the liver.