Inactive urokinase and increased levels of its inhibitor type 1 in colorectal cancer liver metastasis

Abstract

Background/Aims: Human colorectal carcinogenesis was previously found to be associated with an increased urokinase-type plasminogen activator expression, both in antigen and activity, accompanied by simultaneously enhanced levels of plasminogen activator inhibitors type 1 and type 2. This increased proteolytic activity may contribute to invasive growth and metastasis of the tumors. Methods: In the present study, homogenates of liver metastases, primary colorectal carcinomas, and adjacent normal tissues were evaluated regarding the level and composition of urokinase, tissue-type plasminogen activator, and plasminogen activator inhibitors. Results: Concentrations of urokinase were significantly increased in primary carcinomas and liver metastases compared with normal tissues, whereas tissue-type plasminogen activator levels were significantly decreased. Liver metastases showed, in contrast to the carcinomas, hardly any activity of plasminogen activators, which could be attributed to the enhanced presence of the inactive proenzyme form of urokinase in combination with more complexes of plasminogen activators with inhibitors. Furthermore, liver metastases had an eightfold higher content of inhibitor type 1 compared with the primary carcinomas. The excess of inhibitors was confirmed by addition of plasminogen activators to metastasis homogenates, which resulted in increased complex formation. Conclusions: Colorectal cancer metastasis in the liver is associated with an inactivation of the enhanced urokinase cascade, which might allow tumor cells to settle in the liver.